TREM2_HUMAN
ID TREM2_HUMAN Reviewed; 230 AA.
AC Q9NZC2; Q8N5H8; Q8WYN6;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 168.
DE RecName: Full=Triggering receptor expressed on myeloid cells 2;
DE Short=TREM-2;
DE AltName: Full=Triggering receptor expressed on monocytes 2;
DE Flags: Precursor;
GN Name=TREM2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=10799849; DOI=10.4049/jimmunol.164.10.4991;
RA Bouchon A., Dietrich J., Colonna M.;
RT "Inflammatory responses can be triggered by TREM-1, a novel receptor
RT expressed on neutrophils and monocytes.";
RL J. Immunol. 164:4991-4995(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Begum N.A., Tsukasa S.;
RT "Identification of a novel variant of triggering receptor, TREM-2V, by mRNA
RT differential display.";
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION, AND INTERACTION WITH TYROBP.
RX PubMed=11602640; DOI=10.1084/jem.194.8.1111;
RA Bouchon A., Hernandez-Munain C., Cella M., Colonna M.;
RT "A DAP12-mediated pathway regulates expression of CC chemokine receptor 7
RT and maturation of human dendritic cells.";
RL J. Exp. Med. 194:1111-1122(2001).
RN [5]
RP TISSUE SPECIFICITY, INVOLVEMENT IN PLOSL2, AND VARIANTS PLOSL2
RP 44-TRP--THR-230 DEL; 78-TRP--THR-230 DEL; GLY-134 AND ASN-186.
RX PubMed=12080485; DOI=10.1086/342259;
RA Paloneva J., Manninen T., Christman G., Hovanes K., Mandelin J.,
RA Adolfsson R., Bianchin M., Bird T., Miranda R., Salmaggi A.,
RA Tranebjaerg L., Konttinen Y., Peltonen L.;
RT "Mutations in two genes encoding different subunits of a receptor signaling
RT complex result in an identical disease phenotype.";
RL Am. J. Hum. Genet. 71:656-662(2002).
RN [6]
RP ERRATUM OF PUBMED:12080485.
RA Paloneva J., Manninen T., Christman G., Hovanes K., Mandelin J.,
RA Adolfsson R., Bianchin M., Bird T., Miranda R., Salmaggi A.,
RA Tranebjaerg L., Konttinen Y., Peltonen L.;
RL Am. J. Hum. Genet. 72:225-225(2003).
RN [7]
RP FUNCTION, INVOLVEMENT IN PLOSL2, VARIANT PLOSL2 14-GLU--THR-230 DEL, AND
RP CHARACTERIZATION OF VARIANT PLOSL2 14-GLU--THR-230 DEL.
RX PubMed=12925681; DOI=10.1084/jem.20030027;
RA Paloneva J., Mandelin J., Kiialainen A., Bohling T., Prudlo J., Hakola P.,
RA Haltia M., Konttinen Y.T., Peltonen L.;
RT "DAP12/TREM2 deficiency results in impaired osteoclast differentiation and
RT osteoporotic features.";
RL J. Exp. Med. 198:669-675(2003).
RN [8]
RP INVOLVEMENT IN PLOSL2, AND VARIANTS PLOSL2 33-GLN--THR-230 DEL AND GLY-126.
RX PubMed=15883308; DOI=10.1212/01.wnl.0000160304.00003.ca;
RA Kluenemann H.H., Ridha B.H., Magy L., Wherrett J.R., Hemelsoet D.M.,
RA Keen R.W., De Bleecker J.L., Rossor M.N., Marienhagen J., Klein H.E.,
RA Peltonen L., Paloneva J.;
RT "The genetic causes of basal ganglia calcification, dementia, and bone
RT cysts: DAP12 and TREM2.";
RL Neurology 64:1502-1507(2005).
RN [9]
RP FUNCTION.
RX PubMed=18957693; DOI=10.1126/scisignal.1159665;
RA Helming L., Tomasello E., Kyriakides T.R., Martinez F.O., Takai T.,
RA Gordon S., Vivier E.;
RT "Essential role of DAP12 signaling in macrophage programming into a fusion-
RT competent state.";
RL Sci. Signal. 1:RA11-RA11(2008).
RN [10]
RP INTERACTION WITH TYROBP.
RX PubMed=25957402; DOI=10.1074/jbc.m115.645986;
RA Zhong L., Chen X.F., Zhang Z.L., Wang Z., Shi X.Z., Xu K., Zhang Y.W.,
RA Xu H., Bu G.;
RT "DAP12 stabilizes the C-terminal fragment of the triggering receptor
RT expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-
RT inflammatory response.";
RL J. Biol. Chem. 290:15866-15877(2015).
RN [11]
RP SUBCELLULAR LOCATION, AND PROTEOLYTIC PROCESSING.
RX PubMed=24078628; DOI=10.1074/jbc.m113.517540;
RA Wunderlich P., Glebov K., Kemmerling N., Tien N.T., Neumann H., Walter J.;
RT "Sequential proteolytic processing of the triggering receptor expressed on
RT myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-
RT dependent intramembranous cleavage.";
RL J. Biol. Chem. 288:33027-33036(2013).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, CHARACTERIZATION OF
RP VARIANTS CYS-38; HIS-47 AND MET-66, AND MUTAGENESIS OF CYS-36 AND CYS-60.
RX PubMed=24990881; DOI=10.1126/scitranslmed.3009093;
RA Kleinberger G., Yamanishi Y., Suarez-Calvet M., Czirr E., Lohmann E.,
RA Cuyvers E., Struyfs H., Pettkus N., Wenninger-Weinzierl A., Mazaheri F.,
RA Tahirovic S., Lleo A., Alcolea D., Fortea J., Willem M., Lammich S.,
RA Molinuevo J.L., Sanchez-Valle R., Antonell A., Ramirez A., Heneka M.T.,
RA Sleegers K., van der Zee J., Martin J.J., Engelborghs S.,
RA Demirtas-Tatlidede A., Zetterberg H., Van Broeckhoven C., Gurvit H.,
RA Wyss-Coray T., Hardy J., Colonna M., Haass C.;
RT "TREM2 mutations implicated in neurodegeneration impair cell surface
RT transport and phagocytosis.";
RL Sci. Transl. Med. 6:243RA86-243RA86(2014).
RN [13]
RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS MET-27; VAL-28;
RP PHE-31; CYS-38; CYS-47; HIS-47; ASN-87; SER-130; GLN-136; TRP-136; LYS-151;
RP ARG-162 AND ILE-223.
RX PubMed=27589997; DOI=10.1186/s40478-016-0367-7;
RA Sirkis D.W., Bonham L.W., Aparicio R.E., Geier E.G., Ramos E.M., Wang Q.,
RA Karydas A., Miller Z.A., Miller B.L., Coppola G., Yokoyama J.S.;
RT "Rare TREM2 variants associated with Alzheimer's disease display reduced
RT cell surface expression.";
RL Acta Neuropathol. Commun. 4:98-98(2016).
RN [14]
RP VARIANTS TYR-157 AND THR-192, AND VARIANTS CYS-183 AND CYS-200 (ISOFORM 2).
RX PubMed=27067662; DOI=10.1016/j.neurobiolaging.2016.02.023;
RA Jiang T., Tan L., Chen Q., Tan M.S., Zhou J.S., Zhu X.C., Lu H., Wang H.F.,
RA Zhang Y.D., Yu J.T.;
RT "A rare coding variant in TREM2 increases risk for Alzheimer's disease in
RT Han Chinese.";
RL Neurobiol. Aging 42:E1-E3(2016).
RN [15]
RP FUNCTION, TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANTS CYS-38; HIS-47;
RP HIS-62; MET-66 AND ASN-87, AND MUTAGENESIS OF LYS-48.
RX PubMed=27477018; DOI=10.1016/j.neuron.2016.06.015;
RA Yeh F.L., Wang Y., Tom I., Gonzalez L.C., Sheng M.;
RT "TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby
RT Facilitates Uptake of Amyloid-Beta by Microglia.";
RL Neuron 91:328-340(2016).
RN [16]
RP TISSUE SPECIFICITY, AND CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62.
RX PubMed=28802038; DOI=10.1016/j.cell.2017.07.023;
RA Ulland T.K., Song W.M., Huang S.C., Ulrich J.D., Sergushichev A.,
RA Beatty W.L., Loboda A.A., Zhou Y., Cairns N.J., Kambal A., Loginicheva E.,
RA Gilfillan S., Cella M., Virgin H.W., Unanue E.R., Wang Y., Artyomov M.N.,
RA Holtzman D.M., Colonna M.;
RT "TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.";
RL Cell 170:649-663(2017).
RN [17]
RP SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND CHARACTERIZATION OF
RP VARIANT TYR-157.
RX PubMed=28855300; DOI=10.15252/emmm.201707672;
RA Schlepckow K., Kleinberger G., Fukumori A., Feederle R.,
RA Lichtenthaler S.F., Steiner H., Haass C.;
RT "An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and
RT affects shedding and phagocytic function.";
RL EMBO Mol. Med. 9:1356-1365(2017).
RN [18]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, PROTEOLYTIC PROCESSING, AND
RP CHARACTERIZATION OF VARIANT TYR-157.
RX PubMed=28855301; DOI=10.15252/emmm.201707673;
RA Thornton P., Sevalle J., Deery M.J., Fraser G., Zhou Y., Staahl S.,
RA Franssen E.H., Dodd R.B., Qamar S., Gomez Perez-Nievas B., Nicol L.S.,
RA Eketjaell S., Revell J., Jones C., Billinton A., St George-Hyslop P.H.,
RA Chessell I., Crowther D.C.;
RT "TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the
RT Alzheimer's disease-associated H157Y variant.";
RL EMBO Mol. Med. 9:1366-1378(2017).
RN [19]
RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS CYS-38 AND MET-66, AND
RP CHARACTERIZATION OF VARIANTS PLOSL2 GLY-126; GLY-134 AND ASN-186.
RX PubMed=28768830; DOI=10.1091/mbc.e17-06-0423;
RA Sirkis D.W., Aparicio R.E., Schekman R.;
RT "Neurodegeneration-associated mutant TREM2 proteins abortively cycle
RT between the ER and ER-Golgi intermediate compartment.";
RL Mol. Biol. Cell 28:2723-2733(2017).
RN [20]
RP CHARACTERIZATION OF VARIANT HIS-47.
RX PubMed=30442540; DOI=10.1016/j.jalz.2018.09.006;
RA Claes C., Van Den Daele J., Boon R., Schouteden S., Colombo A.,
RA Monasor L.S., Fiers M., Ordovas L., Nami F., Bohrmann B., Tahirovic S.,
RA De Strooper B., Verfaillie C.M.;
RT "Human stem cell-derived monocytes and microglia-like cells reveal impaired
RT amyloid plaque clearance upon heterozygous or homozygous loss of TREM2.";
RL Alzheimers Dement. 15:453-464(2018).
RN [21]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=29752066; DOI=10.1016/j.immuni.2018.04.016;
RA Filipello F., Morini R., Corradini I., Zerbi V., Canzi A., Michalski B.,
RA Erreni M., Markicevic M., Starvaggi-Cucuzza C., Otero K., Piccio L.,
RA Cignarella F., Perrucci F., Tamborini M., Genua M., Rajendran L., Menna E.,
RA Vetrano S., Fahnestock M., Paolicelli R.C., Matteoli M.;
RT "The Microglial Innate Immune Receptor TREM2 Is Required for Synapse
RT Elimination and Normal Brain Connectivity.";
RL Immunity 48:979-991(2018).
RN [22]
RP FUNCTION, AND CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62.
RX PubMed=29518356; DOI=10.1016/j.neuron.2018.01.031;
RA Zhao Y., Wu X., Li X., Jiang L.L., Gui X., Liu Y., Sun Y., Zhu B.,
RA Pina-Crespo J.C., Zhang M., Zhang N., Chen X., Bu G., An Z., Huang T.Y.,
RA Xu H.;
RT "TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function.";
RL Neuron 97:1023-1031(2018).
RN [23] {ECO:0007744|PDB:5ELI}
RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 19-133, DISULFIDE BONDS, SUBUNIT,
RP SUBCELLULAR LOCATION, MUTAGENESIS OF ASN-68; ARG-76 AND ARG-77,
RP GLYCOSYLATION AT ASN-79, CHARACTERIZATION OF VARIANTS CYS-38; HIS-47;
RP HIS-62; MET-66; ASN-87 AND LYS-96, AND CHARACTERIZATION OF VARIANT PLOSL2
RP GLY-126.
RX PubMed=27995897; DOI=10.7554/elife.20391;
RA Kober D.L., Alexander-Brett J.M., Karch C.M., Cruchaga C., Colonna M.,
RA Holtzman M.J., Brett T.J.;
RT "Neurodegenerative disease mutations in TREM2 reveal a functional surface
RT and distinct loss-of-function mechanisms.";
RL Elife 5:E20391-E20391(2016).
RN [24] {ECO:0007744|PDB:6B8O}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 19-174 IN COMPLEX WITH
RP PHOSPHATIDYLSERINE, PHOSPHOLIPID-BINDING, DISULFIDE BONDS, FUNCTION,
RP SUBUNIT, GLYCOSYLATION AT ASN-20 AND ASN-79, CHARACTERIZATION OF VARIANT
RP HIS-47, AND MUTAGENESIS OF ASN-20.
RX PubMed=29794134; DOI=10.1074/jbc.ra118.002352;
RA Sudom A., Talreja S., Danao J., Bragg E., Kegel R., Min X., Richardson J.,
RA Zhang Z., Sharkov N., Marcora E., Thibault S., Bradley J., Wood S.,
RA Lim A.C., Chen H., Wang S., Foltz I.N., Sambashivan S., Wang Z.;
RT "Molecular basis for the loss-of-function effects of the Alzheimer's
RT disease-associated R47H variant of the immune receptor TREM2.";
RL J. Biol. Chem. 293:12634-12646(2018).
RN [25]
RP VARIANT PLOSL2 33-GLN--THR-230 DEL.
RX PubMed=12754369; DOI=10.1136/jnnp.74.6.825-a;
RA Soragna D., Papi L., Ratti M.T., Sestini R., Tupler R., Montalbetti L.;
RT "An Italian family affected by Nasu-Hakola disease with a novel genetic
RT mutation in the TREM2 gene.";
RL J. Neurol. Neurosurg. Psych. 74:825-826(2003).
RN [26]
RP VARIANT PLOSL2 33-GLN--THR-230 DEL.
RX PubMed=23399524; DOI=10.1016/j.jns.2013.01.021;
RA Bock V., Botturi A., Gaviani P., Lamperti E., Maccagnano C., Piccio L.,
RA Silvani A., Salmaggi A.;
RT "Polycystic Lipomembranous Osteodysplasia with Sclerosing
RT Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of
RT the literature.";
RL J. Neurol. Sci. 326:115-119(2013).
RN [27]
RP CHARACTERIZATION OF VARIANT PLOSL2 33-GLN--THR-230 DEL, CHARACTERIZATION OF
RP VARIANTS CYS-38; HIS-47 AND MET-66, AND SUBCELLULAR LOCATION.
RX PubMed=25615530; DOI=10.1111/tra.12264;
RA Park J.S., Ji I.J., An H.J., Kang M.J., Kang S.W., Kim D.H., Yoon S.Y.;
RT "Disease-associated mutations of TREM2 alter the processing of N-linked
RT oligosaccharides in the Golgi apparatus.";
RL Traffic 16:510-518(2015).
RN [28]
RP VARIANT PLOSL2 33-GLN--THR-230 DEL.
RX PubMed=29142083; DOI=10.1212/wnl.0000000000004747;
RA Ghezzi L., Carandini T., Arighi A., Fenoglio C., Arcaro M., De Riz M.,
RA Pietroboni A.M., Fumagalli G.G., Basilico P., Calvi A., Scarioni M.,
RA Colombi A., Serpente M., Marotta G., Benti R., Scarpini E., Galimberti D.;
RT "Evidence of CNS beta-amyloid deposition in Nasu-Hakola disease due to the
RT TREM2 Q33X mutation.";
RL Neurology 89:2503-2505(2017).
CC -!- FUNCTION: Forms a receptor signaling complex with TYROBP which mediates
CC signaling and cell activation following ligand binding
CC (PubMed:10799849). Acts as a receptor for amyloid-beta protein 42, a
CC cleavage product of the amyloid-beta precursor protein APP, and
CC mediates its uptake and degradation by microglia (PubMed:27477018,
CC PubMed:29518356). Binding to amyloid-beta 42 mediates microglial
CC activation, proliferation, migration, apoptosis and expression of pro-
CC inflammatory cytokines, such as IL6R and CCL3, and the anti-
CC inflammatory cytokine ARG1 (By similarity). Acts as a receptor for
CC lipoprotein particles such as LDL, VLDL, and HDL and for
CC apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4,
CC and CLU and enhances their uptake in microglia (PubMed:27477018). Binds
CC phospholipids (preferably anionic lipids) such as phosphatidylserine,
CC phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin
CC (PubMed:29794134). Regulates microglial proliferation by acting as an
CC upstream regulator of the Wnt/beta-catenin signaling cascade (By
CC similarity). Required for microglial phagocytosis of apoptotic neurons
CC (PubMed:24990881). Also required for microglial activation and
CC phagocytosis of myelin debris after neuronal injury and of neuronal
CC synapses during synapse elimination in the developing brain (By
CC similarity). Regulates microglial chemotaxis and process outgrowth, and
CC also the microglial response to oxidative stress and lipopolysaccharide
CC (By similarity). It suppresses PI3K and NF-kappa-B signaling in
CC response to lipopolysaccharide; thus promoting phagocytosis,
CC suppressing pro-inflammatory cytokine and nitric oxide production,
CC inhibiting apoptosis and increasing expression of IL10 and TGFB (By
CC similarity). During oxidative stress, it promotes anti-apoptotic NF-
CC kappa-B signaling and ERK signaling (By similarity). Plays a role in
CC microglial MTOR activation and metabolism (By similarity). Regulates
CC age-related changes in microglial numbers (PubMed:29752066). Triggers
CC activation of the immune responses in macrophages and dendritic cells
CC (PubMed:10799849). Mediates cytokine-induced formation of
CC multinucleated giant cells which are formed by the fusion of
CC macrophages (By similarity). In dendritic cells, it mediates up-
CC regulation of chemokine receptor CCR7 and dendritic cell maturation and
CC survival (PubMed:11602640). Involved in the positive regulation of
CC osteoclast differentiation (PubMed:12925681).
CC {ECO:0000250|UniProtKB:Q99NH8, ECO:0000269|PubMed:10799849,
CC ECO:0000269|PubMed:11602640, ECO:0000269|PubMed:12925681,
CC ECO:0000269|PubMed:24990881, ECO:0000269|PubMed:27477018,
CC ECO:0000269|PubMed:29518356, ECO:0000269|PubMed:29752066,
CC ECO:0000269|PubMed:29794134}.
CC -!- SUBUNIT: Monomer (PubMed:27995897). After ectodomain shedding, the
CC extracellular domain oligomerizes, which is enhanced and stabilized by
CC binding of phosphatidylserine (PubMed:29794134). Interacts with
CC TYROBP/DAP12 (PubMed:11602640, PubMed:25957402). Interaction with
CC TYROBP is required for stabilization of the TREM2 C-terminal fragment
CC (TREM2-CTF) which is produced by proteolytic processing
CC (PubMed:25957402). {ECO:0000269|PubMed:11602640,
CC ECO:0000269|PubMed:25957402, ECO:0000269|PubMed:27995897,
CC ECO:0000269|PubMed:29794134}.
CC -!- INTERACTION:
CC Q9NZC2; P02649: APOE; NbExp=4; IntAct=EBI-14036387, EBI-1222467;
CC Q9NZC2; PRO_0000000092 [P05067]: APP; NbExp=4; IntAct=EBI-14036387, EBI-821758;
CC Q9NZC2; P49768: PSEN1; NbExp=5; IntAct=EBI-14036387, EBI-297277;
CC Q9NZC2; O43914: TYROBP; NbExp=4; IntAct=EBI-14036387, EBI-2214794;
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane
CC {ECO:0000269|PubMed:24078628, ECO:0000269|PubMed:24990881,
CC ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27589997,
CC ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830,
CC ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301}; Single-pass
CC type I membrane protein {ECO:0000255}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9NZC2-1; Sequence=Displayed;
CC Name=2; Synonyms=TREM-2V;
CC IsoId=Q9NZC2-2; Sequence=VSP_010792;
CC Name=3;
CC IsoId=Q9NZC2-3; Sequence=VSP_010793;
CC -!- TISSUE SPECIFICITY: Expressed in the brain, specifically in microglia
CC and in the fusiform gyrus (at protein level) (PubMed:28802038,
CC PubMed:28855300, PubMed:27477018, PubMed:29752066). Expressed on
CC macrophages and dendritic cells but not on granulocytes or monocytes
CC (PubMed:10799849, PubMed:28855301). In the CNS strongest expression
CC seen in the basal ganglia, corpus callosum, medulla oblongata and
CC spinal cord (PubMed:12080485). {ECO:0000269|PubMed:10799849,
CC ECO:0000269|PubMed:12080485, ECO:0000269|PubMed:27477018,
CC ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:28855300,
CC ECO:0000269|PubMed:28855301, ECO:0000269|PubMed:29752066}.
CC -!- PTM: Undergoes ectodomain shedding through proteolytic cleavage by
CC ADAM10 and ADAM17 to produce a transmembrane segment, the TREM2 C-
CC terminal fragment (TREM2-CTF), which is subsequently cleaved by gamma-
CC secretase. {ECO:0000269|PubMed:24078628, ECO:0000269|PubMed:24990881,
CC ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301}.
CC -!- DISEASE: Polycystic lipomembranous osteodysplasia with sclerosing
CC leukoencephalopathy 2 (PLOSL2) [MIM:618193]: An autosomal recessive
CC disease characterized by presenile frontal dementia with
CC leukoencephalopathy and basal ganglia calcification. In most cases the
CC disorder first manifests in early adulthood as pain and swelling in
CC ankles and feet, followed by bone fractures. Neurologic symptoms
CC manifest in the fourth decade of life as a frontal lobe syndrome with
CC loss of judgment, euphoria, and disinhibition. Progressive decline in
CC other cognitive domains begins to develop at about the same time. The
CC disorder culminates in a profound dementia and death by age 50 years.
CC {ECO:0000269|PubMed:12080485, ECO:0000269|PubMed:12754369,
CC ECO:0000269|PubMed:12925681, ECO:0000269|PubMed:15883308,
CC ECO:0000269|PubMed:23399524, ECO:0000269|PubMed:25615530,
CC ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830,
CC ECO:0000269|PubMed:29142083}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB78736.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF213457; AAF69824.1; -; mRNA.
DR EMBL; AB062787; BAB78736.1; ALT_INIT; mRNA.
DR EMBL; BC032362; AAH32362.1; -; mRNA.
DR CCDS; CCDS4852.1; -. [Q9NZC2-1]
DR CCDS; CCDS64422.1; -. [Q9NZC2-2]
DR RefSeq; NP_001258750.1; NM_001271821.1. [Q9NZC2-2]
DR RefSeq; NP_061838.1; NM_018965.3. [Q9NZC2-1]
DR PDB; 5ELI; X-ray; 3.10 A; A/B=19-133.
DR PDB; 5UD7; X-ray; 2.20 A; A/B/C/D/E/F=19-174.
DR PDB; 5UD8; X-ray; 1.80 A; A/B=19-130.
DR PDB; 6B8O; X-ray; 2.20 A; A/B/C/D/E/F=19-174.
DR PDB; 6XDS; X-ray; 1.47 A; A=18-135.
DR PDB; 6Y6C; X-ray; 2.26 A; A/B=19-174.
DR PDB; 6YMQ; X-ray; 3.07 A; D000/G/H/I/J/K=19-131.
DR PDB; 6YYE; X-ray; 3.36 A; A/B=19-131.
DR PDB; 6Z0G; NMR; -; A=161-206.
DR PDB; 6Z0H; NMR; -; A=161-206.
DR PDB; 6Z0I; NMR; -; A=161-206.
DR PDBsum; 5ELI; -.
DR PDBsum; 5UD7; -.
DR PDBsum; 5UD8; -.
DR PDBsum; 6B8O; -.
DR PDBsum; 6XDS; -.
DR PDBsum; 6Y6C; -.
DR PDBsum; 6YMQ; -.
DR PDBsum; 6YYE; -.
DR PDBsum; 6Z0G; -.
DR PDBsum; 6Z0H; -.
DR PDBsum; 6Z0I; -.
DR AlphaFoldDB; Q9NZC2; -.
DR SMR; Q9NZC2; -.
DR BioGRID; 119925; 25.
DR IntAct; Q9NZC2; 6.
DR STRING; 9606.ENSP00000362205; -.
DR TCDB; 9.B.420.1.1; the triggering receptor expressed on myeloid cells 2 (trem2) family.
DR GlyGen; Q9NZC2; 2 sites.
DR iPTMnet; Q9NZC2; -.
DR PhosphoSitePlus; Q9NZC2; -.
DR BioMuta; TREM2; -.
DR DMDM; 50401689; -.
DR jPOST; Q9NZC2; -.
DR MassIVE; Q9NZC2; -.
DR PaxDb; Q9NZC2; -.
DR PeptideAtlas; Q9NZC2; -.
DR PRIDE; Q9NZC2; -.
DR ProteomicsDB; 83358; -. [Q9NZC2-1]
DR ProteomicsDB; 83359; -. [Q9NZC2-2]
DR ProteomicsDB; 83360; -. [Q9NZC2-3]
DR ABCD; Q9NZC2; 4 sequenced antibodies.
DR Antibodypedia; 2280; 571 antibodies from 38 providers.
DR DNASU; 54209; -.
DR Ensembl; ENST00000338469.3; ENSP00000342651.4; ENSG00000095970.17. [Q9NZC2-2]
DR Ensembl; ENST00000373113.8; ENSP00000362205.3; ENSG00000095970.17. [Q9NZC2-1]
DR Ensembl; ENST00000373122.8; ENSP00000362214.4; ENSG00000095970.17. [Q9NZC2-3]
DR GeneID; 54209; -.
DR KEGG; hsa:54209; -.
DR MANE-Select; ENST00000373113.8; ENSP00000362205.3; NM_018965.4; NP_061838.1.
DR UCSC; uc003opy.4; human. [Q9NZC2-1]
DR CTD; 54209; -.
DR DisGeNET; 54209; -.
DR GeneCards; TREM2; -.
DR GeneReviews; TREM2; -.
DR HGNC; HGNC:17761; TREM2.
DR HPA; ENSG00000095970; Tissue enhanced (brain, choroid plexus, lung).
DR MalaCards; TREM2; -.
DR MIM; 605086; gene.
DR MIM; 618193; phenotype.
DR neXtProt; NX_Q9NZC2; -.
DR NIAGADS; ENSG00000095970; -.
DR OpenTargets; ENSG00000095970; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR Orphanet; 2770; Nasu-Hakola disease.
DR Orphanet; 238616; NON RARE IN EUROPE: Alzheimer disease.
DR Orphanet; 100070; Progressive non-fluent aphasia.
DR Orphanet; 100069; Semantic dementia.
DR PharmGKB; PA38468; -.
DR VEuPathDB; HostDB:ENSG00000095970; -.
DR eggNOG; ENOG502S4HV; Eukaryota.
DR GeneTree; ENSGT00470000042297; -.
DR HOGENOM; CLU_076120_0_0_1; -.
DR InParanoid; Q9NZC2; -.
DR OMA; VYGMEGD; -.
DR PhylomeDB; Q9NZC2; -.
DR TreeFam; TF334441; -.
DR PathwayCommons; Q9NZC2; -.
DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR Reactome; R-HSA-2172127; DAP12 interactions.
DR Reactome; R-HSA-2424491; DAP12 signaling.
DR Reactome; R-HSA-416700; Other semaphorin interactions.
DR SignaLink; Q9NZC2; -.
DR BioGRID-ORCS; 54209; 10 hits in 1059 CRISPR screens.
DR ChiTaRS; TREM2; human.
DR GeneWiki; TREM2; -.
DR GenomeRNAi; 54209; -.
DR Pharos; Q9NZC2; Tbio.
DR PRO; PR:Q9NZC2; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q9NZC2; protein.
DR Bgee; ENSG00000095970; Expressed in C1 segment of cervical spinal cord and 132 other tissues.
DR ExpressionAtlas; Q9NZC2; baseline and differential.
DR Genevisible; Q9NZC2; HS.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IDA:BHF-UCL.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:Ensembl.
DR GO; GO:0031226; C:intrinsic component of plasma membrane; IMP:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0044853; C:plasma membrane raft; IDA:ARUK-UCL.
DR GO; GO:0001540; F:amyloid-beta binding; IPI:ARUK-UCL.
DR GO; GO:0034186; F:apolipoprotein A-I binding; IPI:ARUK-UCL.
DR GO; GO:0034185; F:apolipoprotein binding; IPI:ARUK-UCL.
DR GO; GO:0008035; F:high-density lipoprotein particle binding; IDA:ARUK-UCL.
DR GO; GO:0019209; F:kinase activator activity; IMP:ARUK-UCL.
DR GO; GO:0008289; F:lipid binding; TAS:ARUK-UCL.
DR GO; GO:0001530; F:lipopolysaccharide binding; IEA:Ensembl.
DR GO; GO:0071813; F:lipoprotein particle binding; IDA:ARUK-UCL.
DR GO; GO:0070891; F:lipoteichoic acid binding; IEA:Ensembl.
DR GO; GO:0030169; F:low-density lipoprotein particle binding; IDA:ARUK-UCL.
DR GO; GO:0042834; F:peptidoglycan binding; IEA:Ensembl.
DR GO; GO:0008429; F:phosphatidylethanolamine binding; IDA:ARUK-UCL.
DR GO; GO:0001786; F:phosphatidylserine binding; IDA:ARUK-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:UniProtKB.
DR GO; GO:1990782; F:protein tyrosine kinase binding; ISS:ARUK-UCL.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL.
DR GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL.
DR GO; GO:0038023; F:signaling receptor activity; IMP:ARUK-UCL.
DR GO; GO:0120146; F:sulfatide binding; IDA:ARUK-UCL.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; IBA:GO_Central.
DR GO; GO:0034189; F:very-low-density lipoprotein particle binding; IDA:ARUK-UCL.
DR GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; IMP:ARUK-UCL.
DR GO; GO:0043277; P:apoptotic cell clearance; ISS:UniProtKB.
DR GO; GO:0048143; P:astrocyte activation; ISS:ARUK-UCL.
DR GO; GO:1904646; P:cellular response to amyloid-beta; ISS:ARUK-UCL.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0071396; P:cellular response to lipid; IMP:ARUK-UCL.
DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl.
DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; IDA:ARUK-UCL.
DR GO; GO:0071224; P:cellular response to peptidoglycan; IEA:Ensembl.
DR GO; GO:0150062; P:complement-mediated synapse pruning; ISS:ARUK-UCL.
DR GO; GO:0038160; P:CXCL12-activated CXCR4 signaling pathway; IMP:ARUK-UCL.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; ISS:ARUK-UCL.
DR GO; GO:0097028; P:dendritic cell differentiation; IDA:BHF-UCL.
DR GO; GO:0097062; P:dendritic spine maintenance; ISS:ARUK-UCL.
DR GO; GO:0032497; P:detection of lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0070392; P:detection of lipoteichoic acid; IEA:Ensembl.
DR GO; GO:0032499; P:detection of peptidoglycan; IEA:Ensembl.
DR GO; GO:1905805; P:excitatory synapse pruning; ISS:ARUK-UCL.
DR GO; GO:0006959; P:humoral immune response; TAS:ProtInc.
DR GO; GO:0098657; P:import into cell; ISS:ARUK-UCL.
DR GO; GO:0055088; P:lipid homeostasis; ISS:ARUK-UCL.
DR GO; GO:0007613; P:memory; IDA:ARUK-UCL.
DR GO; GO:0001774; P:microglial cell activation; ISS:ARUK-UCL.
DR GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:ARUK-UCL.
DR GO; GO:0061518; P:microglial cell proliferation; ISS:ARUK-UCL.
DR GO; GO:1905907; P:negative regulation of amyloid fibril formation; ISS:ARUK-UCL.
DR GO; GO:0061889; P:negative regulation of astrocyte activation; ISS:ARUK-UCL.
DR GO; GO:1904093; P:negative regulation of autophagic cell death; ISS:ARUK-UCL.
DR GO; GO:0010507; P:negative regulation of autophagy; ISS:ARUK-UCL.
DR GO; GO:0050866; P:negative regulation of cell activation; ISS:ARUK-UCL.
DR GO; GO:0010887; P:negative regulation of cholesterol storage; ISS:ARUK-UCL.
DR GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL.
DR GO; GO:0070345; P:negative regulation of fat cell proliferation; ISS:ARUK-UCL.
DR GO; GO:0034351; P:negative regulation of glial cell apoptotic process; ISS:ARUK-UCL.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; ISS:ARUK-UCL.
DR GO; GO:0002862; P:negative regulation of inflammatory response to antigenic stimulus; ISS:ARUK-UCL.
DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IEA:Ensembl.
DR GO; GO:1902227; P:negative regulation of macrophage colony-stimulating factor signaling pathway; IMP:ARUK-UCL.
DR GO; GO:0150079; P:negative regulation of neuroinflammatory response; IMP:ARUK-UCL.
DR GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; IMP:ARUK-UCL.
DR GO; GO:1903753; P:negative regulation of p38MAPK cascade; ISS:ARUK-UCL.
DR GO; GO:0014067; P:negative regulation of phosphatidylinositol 3-kinase signaling; ISS:ARUK-UCL.
DR GO; GO:0010891; P:negative regulation of sequestering of triglyceride; ISS:ARUK-UCL.
DR GO; GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; ISS:ARUK-UCL.
DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; ISS:ARUK-UCL.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0030316; P:osteoclast differentiation; IMP:UniProtKB.
DR GO; GO:0006911; P:phagocytosis, engulfment; IEA:Ensembl.
DR GO; GO:0006910; P:phagocytosis, recognition; IMP:ARUK-UCL.
DR GO; GO:1900223; P:positive regulation of amyloid-beta clearance; IMP:ARUK-UCL.
DR GO; GO:0002588; P:positive regulation of antigen processing and presentation of peptide antigen via MHC class II; IDA:BHF-UCL.
DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; ISS:ARUK-UCL.
DR GO; GO:1903082; P:positive regulation of C-C chemokine receptor CCR7 signaling pathway; IDA:BHF-UCL.
DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IDA:BHF-UCL.
DR GO; GO:1905291; P:positive regulation of CAMKK-AMPK signaling cascade; ISS:ARUK-UCL.
DR GO; GO:2000350; P:positive regulation of CD40 signaling pathway; IDA:BHF-UCL.
DR GO; GO:0050921; P:positive regulation of chemotaxis; ISS:ARUK-UCL.
DR GO; GO:0010875; P:positive regulation of cholesterol efflux; ISS:ARUK-UCL.
DR GO; GO:0045960; P:positive regulation of complement activation, classical pathway; ISS:ARUK-UCL.
DR GO; GO:1901076; P:positive regulation of engulfment of apoptotic cell; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL.
DR GO; GO:1904951; P:positive regulation of establishment of protein localization; ISS:ARUK-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR GO; GO:0010983; P:positive regulation of high-density lipoprotein particle clearance; ISS:ARUK-UCL.
DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IEA:Ensembl.
DR GO; GO:1901980; P:positive regulation of inward rectifier potassium channel activity; ISS:ARUK-UCL.
DR GO; GO:0033674; P:positive regulation of kinase activity; IDA:ARUK-UCL.
DR GO; GO:1905581; P:positive regulation of low-density lipoprotein particle clearance; ISS:ARUK-UCL.
DR GO; GO:0034241; P:positive regulation of macrophage fusion; ISS:UniProtKB.
DR GO; GO:1903980; P:positive regulation of microglial cell activation; IMP:UniProtKB.
DR GO; GO:1904141; P:positive regulation of microglial cell migration; IMP:ARUK-UCL.
DR GO; GO:0010822; P:positive regulation of mitochondrion organization; ISS:ARUK-UCL.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0050766; P:positive regulation of phagocytosis; IMP:ARUK-UCL.
DR GO; GO:0060100; P:positive regulation of phagocytosis, engulfment; IMP:UniProtKB.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISS:ARUK-UCL.
DR GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; ISS:ARUK-UCL.
DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IDA:BHF-UCL.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:ARUK-UCL.
DR GO; GO:0050714; P:positive regulation of protein secretion; IMP:UniProtKB.
DR GO; GO:1905808; P:positive regulation of synapse pruning; IMP:ARUK-UCL.
DR GO; GO:0032008; P:positive regulation of TOR signaling; ISS:ARUK-UCL.
DR GO; GO:0070269; P:pyroptosis; ISS:ARUK-UCL.
DR GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL.
DR GO; GO:0010468; P:regulation of gene expression; ISS:ARUK-UCL.
DR GO; GO:0110089; P:regulation of hippocampal neuron apoptotic process; ISS:ARUK-UCL.
DR GO; GO:0045088; P:regulation of innate immune response; ISS:ARUK-UCL.
DR GO; GO:0032675; P:regulation of interleukin-6 production; ISS:ARUK-UCL.
DR GO; GO:1902531; P:regulation of intracellular signal transduction; ISS:ARUK-UCL.
DR GO; GO:0019216; P:regulation of lipid metabolic process; IMP:ARUK-UCL.
DR GO; GO:0071640; P:regulation of macrophage inflammatory protein 1 alpha production; ISS:ARUK-UCL.
DR GO; GO:1903376; P:regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; ISS:ARUK-UCL.
DR GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; ISS:ARUK-UCL.
DR GO; GO:0120035; P:regulation of plasma membrane bounded cell projection organization; IGI:ARUK-UCL.
DR GO; GO:0060075; P:regulation of resting membrane potential; ISS:ARUK-UCL.
DR GO; GO:0034151; P:regulation of toll-like receptor 6 signaling pathway; ISS:ARUK-UCL.
DR GO; GO:0032006; P:regulation of TOR signaling; ISS:ARUK-UCL.
DR GO; GO:0045728; P:respiratory burst after phagocytosis; ISS:ARUK-UCL.
DR GO; GO:0048678; P:response to axon injury; IMP:ARUK-UCL.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0035176; P:social behavior; IMP:ARUK-UCL.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013106; Ig_V-set.
DR Pfam; PF07686; V-set; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Disease variant;
KW Disulfide bond; Glycoprotein; Immunoglobulin domain; Lipid-binding;
KW Membrane; Neurodegeneration; Receptor; Reference proteome; Secreted;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..230
FT /note="Triggering receptor expressed on myeloid cells 2"
FT /id="PRO_0000014987"
FT TOPO_DOM 19..174
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 175..195
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 196..230
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 29..112
FT /note="Ig-like V-type"
FT BINDING 67
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000269|PubMed:29794134,
FT ECO:0007744|PDB:6B8O"
FT BINDING 68
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000269|PubMed:29794134,
FT ECO:0007744|PDB:6B8O"
FT BINDING 77
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000269|PubMed:29794134,
FT ECO:0007744|PDB:6B8O"
FT BINDING 88
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000269|PubMed:29794134,
FT ECO:0007744|PDB:6B8O"
FT SITE 157..158
FT /note="Cleavage of ectodomain"
FT /evidence="ECO:0000269|PubMed:28855300,
FT ECO:0000269|PubMed:28855301"
FT CARBOHYD 20
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:29794134,
FT ECO:0007744|PDB:6B8O"
FT CARBOHYD 79
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:27995897,
FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI,
FT ECO:0007744|PDB:6B8O"
FT DISULFID 36..110
FT /evidence="ECO:0000269|PubMed:27995897,
FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI,
FT ECO:0007744|PDB:5UD7, ECO:0007744|PDB:5UD8,
FT ECO:0007744|PDB:6B8O"
FT DISULFID 51..60
FT /evidence="ECO:0000269|PubMed:27995897,
FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI,
FT ECO:0007744|PDB:5UD8, ECO:0007744|PDB:6B8O"
FT VAR_SEQ 162..230
FT /note="SLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDC
FT GHDPGYQLQTLPGLRDT -> AERHVKEDDGRKSPGEVPPGTSPACILATWPPGLLVLL
FT WQETTLPEHCFSWTLEAGTG (in isoform 2)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_010792"
FT VAR_SEQ 162..230
FT /note="SLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDC
FT GHDPGYQLQTLPGLRDT -> PSQGSHLPSCLSKEPLGRRNPLPTHFHPSPPGLHLSHQ
FT DSSSQRPLGCSLAWTEARDTSTQ (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_010793"
FT VARIANT 14..230
FT /note="Missing (in PLOSL2; results in decreased osteoclast
FT differentiation; no TREM2 transcripts can be detected in
FT patient cells homozygous for the variant)"
FT /evidence="ECO:0000269|PubMed:12925681"
FT /id="VAR_081676"
FT VARIANT 27
FT /note="V -> M (found in patients with late onset Alzheimer
FT disease; unknown pathological significance; no effect on
FT cell membrane localization; dbSNP:rs768745050)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081812"
FT VARIANT 28
FT /note="A -> V (found in patients with late onset Alzheimer
FT disease; unknown pathological significance; increases cell
FT membrane localization; dbSNP:rs2234252)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081813"
FT VARIANT 31
FT /note="S -> F (found in patients with late onset Alzheimer
FT disease; unknown pathological significance; decreases cell
FT membrane localization; dbSNP:rs746216516)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081814"
FT VARIANT 33..230
FT /note="Missing (in PLOSL2; no protein detected by Wester
FT blot)"
FT /evidence="ECO:0000269|PubMed:12754369,
FT ECO:0000269|PubMed:15883308, ECO:0000269|PubMed:23399524,
FT ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:29142083"
FT /id="VAR_081677"
FT VARIANT 38
FT /note="Y -> C (results in defective protein maturation and
FT trafficking; loss of proteolytic cleavage by ADAM10 and
FT ectodomain shedding; increases protein aggregation;
FT decreases cell membrane localization; decreased
FT phagocytosis; loss of LDL, CLU and APOE binding; greatly
FT decreases LDL and CLU uptake into cells;
FT dbSNP:rs797044603)"
FT /evidence="ECO:0000269|PubMed:24990881,
FT ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018,
FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897,
FT ECO:0000269|PubMed:28768830"
FT /id="VAR_081815"
FT VARIANT 44..230
FT /note="Missing (in PLOSL2)"
FT /evidence="ECO:0000269|PubMed:12080485"
FT /id="VAR_081678"
FT VARIANT 47
FT /note="R -> C (found in patients with late onset Alzheimer
FT disease; unknown pathological significance; decreases cell
FT membrane localization; dbSNP:rs753325601)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081816"
FT VARIANT 47
FT /note="R -> H (found in patients with late onset Alzheimer
FT disease; unknown pathological significance; no effect on
FT cell membrane localization; no effect on autophagy in
FT microglia; no effect on phagocystosis, including amyloid
FT plaque clearance by microglia; reduces ectodomain shedding
FT caused by proteolytic cleavage by ADAM10, while also
FT reducing the oligomerization of the extracellular domain
FT after shedding; decreases binding to and uptake of LDL and
FT CLU into cells; decreases binding to APOE, phospholipids
FT and oligomeric APP cleavage product beta-amyloid peptide
FT 42; dbSNP:rs75932628)"
FT /evidence="ECO:0000269|PubMed:24990881,
FT ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018,
FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897,
FT ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:29518356,
FT ECO:0000269|PubMed:29794134, ECO:0000269|PubMed:30442540"
FT /id="VAR_081817"
FT VARIANT 62
FT /note="R -> H (does not affect protein structure; no effect
FT on cell membrane localization; increases autophagy in
FT microglia; decreases LDL, CLU and APOE binding; decreases
FT LDL uptake into cells; no effect on CLU uptake into cells;
FT decreases the uptake of APP-LDL complex in macrophages;
FT decreases binding to oligomeric APP cleavage product beta-
FT amyloid peptide 42; dbSNP:rs143332484)"
FT /evidence="ECO:0000269|PubMed:27477018,
FT ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28802038,
FT ECO:0000269|PubMed:29518356"
FT /id="VAR_081818"
FT VARIANT 66
FT /note="T -> M (results in defective protein maturation and
FT trafficking; loss of proteolytic cleavage by ADAM10 and
FT ectodomain shedding; increases protein aggregation;
FT decreases cell membrane localization; decreases
FT phagocytosis; loss of LDL, CLU and APOE binding; greatly
FT decreases LDL and CLU uptake into cells;
FT dbSNP:rs201258663)"
FT /evidence="ECO:0000269|PubMed:24990881,
FT ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018,
FT ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830"
FT /id="VAR_081819"
FT VARIANT 78..230
FT /note="Missing (in PLOSL2)"
FT /evidence="ECO:0000269|PubMed:12080485"
FT /id="VAR_081679"
FT VARIANT 87
FT /note="D -> N (decreases LDL, CLU and APOE binding;
FT decreases LDL and CLU uptake into cells; no effect on cell
FT membrane localization; dbSNP:rs142232675)"
FT /evidence="ECO:0000269|PubMed:27477018,
FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897"
FT /id="VAR_081820"
FT VARIANT 96
FT /note="T -> K (does not change protein structure; changes
FT protein stability; increases binding to THP-1 cells;
FT dbSNP:rs2234253)"
FT /evidence="ECO:0000269|PubMed:27995897"
FT /id="VAR_061329"
FT VARIANT 96
FT /note="T -> R (in dbSNP:rs2234253)"
FT /id="VAR_061330"
FT VARIANT 126
FT /note="V -> G (in PLOSL2; results in defective protein
FT maturation; increases protein aggregation; decreases cell
FT membrane localization; dbSNP:rs121908402)"
FT /evidence="ECO:0000269|PubMed:15883308,
FT ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830"
FT /id="VAR_081680"
FT VARIANT 130
FT /note="A -> S (likely benign variant; no effect on protein
FT expression and maturation)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081821"
FT VARIANT 134
FT /note="D -> G (in PLOSL2; unknown pathological
FT significance; decreased protein level; dbSNP:rs28939079)"
FT /evidence="ECO:0000269|PubMed:12080485,
FT ECO:0000269|PubMed:28768830"
FT /id="VAR_019334"
FT VARIANT 136
FT /note="R -> Q (found in patients with Alzheimer disease;
FT unknown pathological significance; slightly decreases cell
FT membrane localization; dbSNP:rs149622783)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081822"
FT VARIANT 136
FT /note="R -> W (found in patients with Alzheimer disease;
FT unknown pathological significance; decreases cell membrane
FT localization; dbSNP:rs772641807)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081823"
FT VARIANT 151
FT /note="E -> K (found in patients with late onset Alzheimer
FT disease; unknown pathological significance; decreases cell
FT membrane localization; dbSNP:rs79011726)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081824"
FT VARIANT 157
FT /note="H -> Y (may be associated with an increased risk for
FT late-onset Alzheimer disease; accelerates ectodomain
FT shedding but does not alter the cleavage site; decreases
FT cell membrane localization; decreases phagocytosis;
FT dbSNP:rs2234255)"
FT /evidence="ECO:0000269|PubMed:27067662,
FT ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301"
FT /id="VAR_033625"
FT VARIANT 162
FT /note="S -> R (no effect on protein expression and
FT maturation; dbSNP:rs371702633)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081825"
FT VARIANT 186
FT /note="K -> N (in PLOSL2; unknown pathological
FT significance; increased localization at the cell membrane;
FT dbSNP:rs28937876)"
FT /evidence="ECO:0000269|PubMed:12080485,
FT ECO:0000269|PubMed:28768830"
FT /id="VAR_019335"
FT VARIANT 192
FT /note="A -> T (in dbSNP:rs150277350)"
FT /evidence="ECO:0000269|PubMed:27067662"
FT /id="VAR_077696"
FT VARIANT 211
FT /note="L -> P (in dbSNP:rs2234256)"
FT /id="VAR_033626"
FT VARIANT 223
FT /note="T -> I (affects protein maturation;
FT dbSNP:rs138355759)"
FT /evidence="ECO:0000269|PubMed:27589997"
FT /id="VAR_081826"
FT MUTAGEN 20
FT /note="N->D: Loss of glycosylation."
FT /evidence="ECO:0000269|PubMed:29794134"
FT MUTAGEN 36
FT /note="C->A: Loss of proteolytic cleavage by ADAM10 and
FT ectodomain shedding. Decreases protein maturation and cell
FT membrane localization."
FT /evidence="ECO:0000269|PubMed:24990881"
FT MUTAGEN 48
FT /note="K->M: Loss of LDL, CLU and APOE binding."
FT /evidence="ECO:0000269|PubMed:27477018"
FT MUTAGEN 60
FT /note="C->A: Loss of proteolytic cleavage by ADAM10 and
FT ectodomain shedding. Decreases protein maturation and cell
FT membrane localization."
FT /evidence="ECO:0000269|PubMed:24990881"
FT MUTAGEN 68
FT /note="N->K: No effect on cell membrane localization."
FT /evidence="ECO:0000269|PubMed:27995897"
FT MUTAGEN 76
FT /note="R->D: Decreases binding to THP-1 cells."
FT /evidence="ECO:0000269|PubMed:27995897"
FT MUTAGEN 77
FT /note="R->D: Decreases binding to THP-1 cells."
FT /evidence="ECO:0000269|PubMed:27995897"
FT STRAND 19..27
FT /evidence="ECO:0007829|PDB:6XDS"
FT STRAND 32..37
FT /evidence="ECO:0007829|PDB:6XDS"
FT TURN 40..45
FT /evidence="ECO:0007829|PDB:6XDS"
FT STRAND 48..53
FT /evidence="ECO:0007829|PDB:6XDS"
FT TURN 55..57
FT /evidence="ECO:0007829|PDB:6XDS"
FT STRAND 60..65
FT /evidence="ECO:0007829|PDB:6XDS"
FT HELIX 70..72
FT /evidence="ECO:0007829|PDB:6B8O"
FT STRAND 74..77
FT /evidence="ECO:0007829|PDB:6XDS"
FT STRAND 80..87
FT /evidence="ECO:0007829|PDB:6XDS"
FT TURN 88..91
FT /evidence="ECO:0007829|PDB:6XDS"
FT STRAND 92..99
FT /evidence="ECO:0007829|PDB:6XDS"
FT HELIX 102..104
FT /evidence="ECO:0007829|PDB:6XDS"
FT STRAND 106..114
FT /evidence="ECO:0007829|PDB:6XDS"
FT STRAND 117..129
FT /evidence="ECO:0007829|PDB:6XDS"
FT HELIX 132..135
FT /evidence="ECO:0007829|PDB:6XDS"
FT HELIX 163..165
FT /evidence="ECO:0007829|PDB:6Z0G"
FT HELIX 172..189
FT /evidence="ECO:0007829|PDB:6Z0G"
FT HELIX 191..198
FT /evidence="ECO:0007829|PDB:6Z0G"
FT VARIANT Q9NZC2-2:183
FT /note="S -> C (in dbSNP:rs200820365)"
FT /evidence="ECO:0000269|PubMed:27067662"
FT /id="VAR_082839"
FT VARIANT Q9NZC2-2:200
FT /note="W -> C (in dbSNP:rs1391283629)"
FT /evidence="ECO:0000269|PubMed:27067662"
FT /id="VAR_082840"
SQ SEQUENCE 230 AA; 25447 MW; C894AA210F708AF7 CRC64;
MEPLRLLILL FVTELSGAHN TTVFQGVAGQ SLQVSCPYDS MKHWGRRKAW CRQLGEKGPC
QRVVSTHNLW LLSFLRRWNG STAITDDTLG GTLTITLRNL QPHDAGLYQC QSLHGSEADT
LRKVLVEVLA DPLDHRDAGD LWFPGESESF EDAHVEHSIS RSLLEGEIPF PPTSILLLLA
CIFLIKILAA SALWAAAWHG QKPGTHPPSE LDCGHDPGYQ LQTLPGLRDT
