AP4M1_HUMAN
ID AP4M1_HUMAN Reviewed; 453 AA.
AC O00189; D6W5U1; Q8WV65; Q9UHK9;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=AP-4 complex subunit mu-1 {ECO:0000305};
DE AltName: Full=AP-4 adaptor complex mu subunit;
DE AltName: Full=Adaptor-related protein complex 4 subunit mu-1;
DE AltName: Full=Mu subunit of AP-4;
DE AltName: Full=Mu-adaptin-related protein 2;
DE Short=mu-ARP2;
DE AltName: Full=Mu4-adaptin;
DE Short=mu4;
GN Name=AP4M1 {ECO:0000312|HGNC:HGNC:574}; Synonyms=MUARP2;
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], AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=9013859; DOI=10.1016/s0014-5793(96)01500-1;
RA Wang X., Kilimann M.W.;
RT "Identification of two new mu-adaptin-related proteins, mu-ARP1 and mu-
RT ARP2.";
RL FEBS Lett. 402:57-61(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBUNIT.
RC TISSUE=Brain;
RX PubMed=10436028; DOI=10.1091/mbc.10.8.2787;
RA Hirst J., Bright N.A., Rous B., Robinson M.S.;
RT "Characterization of a fourth adaptor-related protein complex.";
RL Mol. Biol. Cell 10:2787-2802(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH LAMP2, AND
RP SUBCELLULAR LOCATION.
RC TISSUE=Spleen;
RX PubMed=11139587; DOI=10.1074/jbc.m010591200;
RA Aguilar R.C., Boehm M., Gorshkova I., Crouch R.J., Tomita K., Saito T.,
RA Ohno H., Bonifacino J.S.;
RT "Signal-binding specificity of the mu4 subunit of the adaptor protein
RT complex, AP-4.";
RL J. Biol. Chem. 276:13145-13152(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP FUNCTION, AND SUBUNIT.
RX PubMed=10066790; DOI=10.1074/jbc.274.11.7278;
RA Dell'Angelica E.C., Mullins C., Bonifacino J.S.;
RT "AP-4, a novel protein complex related to clathrin adaptors.";
RL J. Biol. Chem. 274:7278-7285(1999).
RN [7]
RP INVOLVEMENT IN SPG50.
RX PubMed=19559397; DOI=10.1016/j.ajhg.2009.06.004;
RA Verkerk A.J., Schot R., Dumee B., Schellekens K., Swagemakers S.,
RA Bertoli-Avella A.M., Lequin M.H., Dudink J., Govaert P., van Zwol A.L.,
RA Hirst J., Wessels M.W., Catsman-Berrevoets C., Verheijen F.W.,
RA de Graaff E., de Coo I.F., Kros J.M., Willemsen R., Willems P.J.,
RA van der Spek P.J., Mancini G.M.;
RT "Mutation in the AP4M1 gene provides a model for neuroaxonal injury in
RT cerebral palsy.";
RL Am. J. Hum. Genet. 85:40-52(2009).
RN [8]
RP FUNCTION, AND SUBUNIT.
RX PubMed=11802162; DOI=10.1038/ncb745;
RA Simmen T., Hoening S., Icking A., Tikkanen R., Hunziker W.;
RT "AP-4 binds basolateral signals and participates in basolateral sorting in
RT epithelial MDCK cells.";
RL Nat. Cell Biol. 4:154-159(2002).
RN [9]
RP FUNCTION, AND INTERACTION WITH NAGPA.
RX PubMed=26544806; DOI=10.1016/j.ajhg.2015.10.007;
RA Raza M.H., Mattera R., Morell R., Sainz E., Rahn R., Gutierrez J.,
RA Paris E., Root J., Solomon B., Brewer C., Basra M.A., Khan S.,
RA Riazuddin S., Braun A., Bonifacino J.S., Drayna D.;
RT "Association between rare variants in AP4E1, a component of intracellular
RT trafficking, and persistent stuttering.";
RL Am. J. Hum. Genet. 97:715-725(2015).
RN [10]
RP INTERACTION WITH ATG9A, AND SUBCELLULAR LOCATION.
RX PubMed=29180427; DOI=10.1073/pnas.1717327114;
RA Mattera R., Park S.Y., De Pace R., Guardia C.M., Bonifacino J.S.;
RT "AP-4 mediates export of ATG9A from the trans-Golgi network to promote
RT autophagosome formation.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:E10697-E10706(2017).
RN [11]
RP INTERACTION WITH HOOK1 AND HOOK2, AND SUBCELLULAR LOCATION.
RX PubMed=32073997; DOI=10.1091/mbc.e19-11-0658;
RA Mattera R., Williamson C.D., Ren X., Bonifacino J.S.;
RT "The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear
RT distribution of AP-4 and its cargo ATG9A.";
RL Mol. Biol. Cell 31:963-979(2020).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 160-453 IN COMPLEX WITH APP
RP PEPTIDE, FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF PHE-255 AND
RP ARG-283, AND SUBUNIT.
RX PubMed=20230749; DOI=10.1016/j.devcel.2010.01.015;
RA Burgos P.V., Mardones G.A., Rojas A.L., daSilva L.L., Prabhu Y.,
RA Hurley J.H., Bonifacino J.S.;
RT "Sorting of the Alzheimer's disease amyloid precursor protein mediated by
RT the AP-4 complex.";
RL Dev. Cell 18:425-436(2010).
CC -!- FUNCTION: Component of the adaptor protein complex 4 (AP-4). Adaptor
CC protein complexes are vesicle coat components involved both in vesicle
CC formation and cargo selection. They control the vesicular transport of
CC proteins in different trafficking pathways (PubMed:10436028,
CC PubMed:11139587, PubMed:10066790, PubMed:11802162, PubMed:20230749).
CC AP-4 forms a non clathrin-associated coat on vesicles departing the
CC trans-Golgi network (TGN) and may be involved in the targeting of
CC proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal
CC system (PubMed:11139587, PubMed:20230749). It is also involved in
CC protein sorting to the basolateral membrane in epithelial cells and the
CC proper asymmetric localization of somatodendritic proteins in neurons
CC (By similarity). Within AP-4, the mu-type subunit AP4M1 is directly
CC involved in the recognition and binding of tyrosine-based sorting
CC signals found in the cytoplasmic part of cargos (PubMed:10436028,
CC PubMed:11139587, PubMed:26544806, PubMed:20230749). The adaptor protein
CC complex 4 (AP-4) may also recognize other types of sorting signal (By
CC similarity). {ECO:0000250|UniProtKB:E2RED8,
CC ECO:0000250|UniProtKB:Q2PWT8, ECO:0000250|UniProtKB:Q9JKC7,
CC ECO:0000269|PubMed:10066790, ECO:0000269|PubMed:10436028,
CC ECO:0000269|PubMed:11139587, ECO:0000269|PubMed:11802162,
CC ECO:0000269|PubMed:20230749, ECO:0000269|PubMed:26544806}.
CC -!- SUBUNIT: Adaptor protein complex 4 (AP-4) is a heterotetramer composed
CC of two large adaptins (epsilon-type subunit AP4E1 and beta-type subunit
CC AP4B1), a medium adaptin (mu-type subunit AP4M1) and a small adaptin
CC (sigma-type AP4S1) (PubMed:10436028, PubMed:10066790, PubMed:11802162).
CC Interacts with tyrosine-based sorting signals on the cytoplasmic tail
CC of cargo proteins such as APP, ATG9A, LAMP2 and NAGPA (PubMed:11139587,
CC PubMed:26544806, PubMed:29180427, PubMed:20230749). Interacts with the
CC C-terminal domain of GRID2 (By similarity). Interacts with GRIA1 and
CC GRIA2; the interaction is indirect via CACNG3 (By similarity).
CC Interacts with CACNG3; CACNG3 associates GRIA1 and GRIA2 with the
CC adaptor protein complex 4 (AP-4) to target them to the somatodendritic
CC compartment of neurons (By similarity). Interacts with HOOK1 and HOOK2;
CC the interactions are direct, mediate the interaction between FTS-Hook-
CC FHIP (FHF) complex and AP-4 and the perinuclear distribution of AP-4
CC (PubMed:32073997). {ECO:0000250|UniProtKB:Q2PWT8,
CC ECO:0000250|UniProtKB:Q9JKC7, ECO:0000269|PubMed:10066790,
CC ECO:0000269|PubMed:10436028, ECO:0000269|PubMed:11139587,
CC ECO:0000269|PubMed:11802162, ECO:0000269|PubMed:20230749,
CC ECO:0000269|PubMed:26544806, ECO:0000269|PubMed:29180427,
CC ECO:0000269|PubMed:32073997}.
CC -!- INTERACTION:
CC O00189; P49354: FNTA; NbExp=3; IntAct=EBI-3914106, EBI-602336;
CC O00189; Q96K76: USP47; NbExp=3; IntAct=EBI-3914106, EBI-2514143;
CC O00189; Q96K76-3: USP47; NbExp=3; IntAct=EBI-3914106, EBI-12313025;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network membrane
CC {ECO:0000269|PubMed:20230749, ECO:0000269|PubMed:29180427,
CC ECO:0000269|PubMed:32073997}; Peripheral membrane protein
CC {ECO:0000305|PubMed:32073997}. Early endosome
CC {ECO:0000269|PubMed:20230749}. Note=Found in soma and dendritic shafts
CC of neuronal cells. {ECO:0000250|UniProtKB:Q2PWT8}.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Highly expressed in testis and lowly
CC expressed in brain and lung. {ECO:0000269|PubMed:9013859}.
CC -!- DISEASE: Spastic paraplegia 50, autosomal recessive (SPG50)
CC [MIM:612936]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness and
CC spasticity of the lower limbs. Rate of progression and the severity of
CC symptoms are quite variable. Initial symptoms may include difficulty
CC with balance, weakness and stiffness in the legs, muscle spasms, and
CC dragging the toes when walking. In some forms of the disorder, bladder
CC symptoms (such as incontinence) may appear, or the weakness and
CC stiffness may spread to other parts of the body. SPG50 affected
CC individuals present postnatally with early infantile hypotonia, delayed
CC psychomotor development, strabismus, lack of independent walking and
CC severe intellectual disability. They develop progressive spasticity of
CC all limbs with generalized hypertonia, hyperreflexia, and extensor
CC plantar responses by the end of the first year of life. Speech is
CC absent or limited. Pseudobulbar signs, such as drooling, stereotypic
CC laughter, and exaggerated jaw jerk, are part of the clinical picture.
CC {ECO:0000269|PubMed:19559397}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the adaptor complexes medium subunit family.
CC {ECO:0000305}.
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DR EMBL; Y08387; CAA69667.1; -; mRNA.
DR EMBL; AF155158; AAD43328.1; -; mRNA.
DR EMBL; AF020796; AAD25869.1; -; mRNA.
DR EMBL; CH471091; EAW76594.1; -; Genomic_DNA.
DR EMBL; CH471091; EAW76597.1; -; Genomic_DNA.
DR EMBL; BC018705; AAH18705.1; -; mRNA.
DR CCDS; CCDS5685.1; -.
DR RefSeq; NP_004713.2; NM_004722.3.
DR PDB; 3L81; X-ray; 1.60 A; A=160-453.
DR PDB; 4MDR; X-ray; 1.85 A; A=160-453.
DR PDBsum; 3L81; -.
DR PDBsum; 4MDR; -.
DR AlphaFoldDB; O00189; -.
DR SMR; O00189; -.
DR BioGRID; 114616; 45.
DR ComplexPortal; CPX-5151; AP-4 Adaptor complex.
DR CORUM; O00189; -.
DR IntAct; O00189; 32.
DR MINT; O00189; -.
DR STRING; 9606.ENSP00000352603; -.
DR TCDB; 9.B.278.1.5; the organellar-targeting adaptor protein complex (o-apc) family.
DR iPTMnet; O00189; -.
DR PhosphoSitePlus; O00189; -.
DR BioMuta; AP4M1; -.
DR EPD; O00189; -.
DR jPOST; O00189; -.
DR MassIVE; O00189; -.
DR MaxQB; O00189; -.
DR PaxDb; O00189; -.
DR PeptideAtlas; O00189; -.
DR PRIDE; O00189; -.
DR ProteomicsDB; 47769; -.
DR TopDownProteomics; O00189; -.
DR Antibodypedia; 30540; 174 antibodies from 25 providers.
DR DNASU; 9179; -.
DR Ensembl; ENST00000359593.9; ENSP00000352603.4; ENSG00000221838.10.
DR Ensembl; ENST00000421755.5; ENSP00000412185.1; ENSG00000221838.10.
DR GeneID; 9179; -.
DR KEGG; hsa:9179; -.
DR MANE-Select; ENST00000359593.9; ENSP00000352603.4; NM_004722.4; NP_004713.2.
DR UCSC; uc003utb.5; human.
DR CTD; 9179; -.
DR DisGeNET; 9179; -.
DR GeneCards; AP4M1; -.
DR GeneReviews; AP4M1; -.
DR HGNC; HGNC:574; AP4M1.
DR HPA; ENSG00000221838; Low tissue specificity.
DR MalaCards; AP4M1; -.
DR MIM; 602296; gene.
DR MIM; 612936; phenotype.
DR neXtProt; NX_O00189; -.
DR OpenTargets; ENSG00000221838; -.
DR Orphanet; 280763; Severe intellectual disability and progressive spastic paraplegia.
DR PharmGKB; PA24866; -.
DR VEuPathDB; HostDB:ENSG00000221838; -.
DR eggNOG; KOG0937; Eukaryota.
DR GeneTree; ENSGT00940000159929; -.
DR InParanoid; O00189; -.
DR OMA; NVCATIP; -.
DR PhylomeDB; O00189; -.
DR TreeFam; TF329745; -.
DR PathwayCommons; O00189; -.
DR Reactome; R-HSA-432720; Lysosome Vesicle Biogenesis.
DR SignaLink; O00189; -.
DR BioGRID-ORCS; 9179; 9 hits in 1085 CRISPR screens.
DR ChiTaRS; AP4M1; human.
DR EvolutionaryTrace; O00189; -.
DR GeneWiki; AP4M1; -.
DR GenomeRNAi; 9179; -.
DR Pharos; O00189; Tbio.
DR PRO; PR:O00189; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; O00189; protein.
DR Bgee; ENSG00000221838; Expressed in left testis and 109 other tissues.
DR ExpressionAtlas; O00189; baseline and differential.
DR Genevisible; O00189; HS.
DR GO; GO:0030124; C:AP-4 adaptor complex; IDA:UniProtKB.
DR GO; GO:0030131; C:clathrin adaptor complex; IEA:InterPro.
DR GO; GO:0031410; C:cytoplasmic vesicle; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IEA:GOC.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0031904; C:endosome lumen; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB.
DR GO; GO:0032588; C:trans-Golgi network membrane; TAS:Reactome.
DR GO; GO:0019904; F:protein domain specific binding; IDA:UniProtKB.
DR GO; GO:0008320; F:protein transmembrane transporter activity; TAS:Reactome.
DR GO; GO:0000045; P:autophagosome assembly; IMP:UniProtKB.
DR GO; GO:0006895; P:Golgi to endosome transport; IMP:UniProtKB.
DR GO; GO:0090160; P:Golgi to lysosome transport; IDA:UniProtKB.
DR GO; GO:0006886; P:intracellular protein transport; IMP:UniProtKB.
DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; TAS:Reactome.
DR GO; GO:0008104; P:protein localization; ISS:UniProtKB.
DR GO; GO:1903361; P:protein localization to basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0006605; P:protein targeting; IDA:UniProtKB.
DR GO; GO:0006622; P:protein targeting to lysosome; IDA:UniProtKB.
DR GO; GO:0016192; P:vesicle-mediated transport; IBA:GO_Central.
DR InterPro; IPR036168; AP2_Mu_C_sf.
DR InterPro; IPR022775; AP_mu_sigma_su.
DR InterPro; IPR001392; Clathrin_mu.
DR InterPro; IPR018240; Clathrin_mu_CS.
DR InterPro; IPR011012; Longin-like_dom_sf.
DR InterPro; IPR028565; MHD.
DR Pfam; PF00928; Adap_comp_sub; 1.
DR Pfam; PF01217; Clat_adaptor_s; 1.
DR PIRSF; PIRSF005992; Clathrin_mu; 1.
DR PRINTS; PR00314; CLATHRINADPT.
DR SUPFAM; SSF49447; SSF49447; 1.
DR SUPFAM; SSF64356; SSF64356; 1.
DR PROSITE; PS00991; CLAT_ADAPTOR_M_2; 1.
DR PROSITE; PS51072; MHD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Endosome; Golgi apparatus; Hereditary spastic paraplegia;
KW Membrane; Neurodegeneration; Protein transport; Reference proteome;
KW Transport.
FT CHAIN 1..453
FT /note="AP-4 complex subunit mu-1"
FT /id="PRO_0000193787"
FT DOMAIN 184..452
FT /note="MHD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00404"
FT MUTAGEN 255
FT /note="F->A: Abolishes interaction with APP."
FT /evidence="ECO:0000269|PubMed:20230749"
FT MUTAGEN 283
FT /note="R->D: Strongly reduced interaction with APP."
FT /evidence="ECO:0000269|PubMed:20230749"
FT CONFLICT 338
FT /note="R -> G (in Ref. 2; AAD43328)"
FT /evidence="ECO:0000305"
FT CONFLICT 345
FT /note="Q -> R (in Ref. 1; CAA69667 and 3; AAD25869)"
FT /evidence="ECO:0000305"
FT CONFLICT 400
FT /note="L -> M (in Ref. 2; AAD43328)"
FT /evidence="ECO:0000305"
FT CONFLICT 417
FT /note="S -> C (in Ref. 2; AAD43328)"
FT /evidence="ECO:0000305"
FT STRAND 186..199
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 205..218
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 225..230
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 235..237
FT /evidence="ECO:0007829|PDB:3L81"
FT TURN 240..242
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 246..256
FT /evidence="ECO:0007829|PDB:3L81"
FT HELIX 264..267
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 269..272
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 276..286
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 295..304
FT /evidence="ECO:0007829|PDB:3L81"
FT TURN 306..308
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 309..319
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 326..335
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 341..349
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 353..357
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 360..365
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 373..381
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 405..412
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 421..427
FT /evidence="ECO:0007829|PDB:3L81"
FT STRAND 437..451
FT /evidence="ECO:0007829|PDB:3L81"
SQ SEQUENCE 453 AA; 49977 MW; AE3DCA8C5AED08B7 CRC64;
MISQFFILSS KGDPLIYKDF RGDSGGRDVA ELFYRKLTGL PGDESPVVMH HHGRHFIHIR
HSGLYLVVTT SENVSPFSLL ELLSRLATLL GDYCGSLGEG TISRNVALVY ELLDEVLDYG
YVQTTSTEML RNFIQTEAVV SKPFSLFDLS SVGLFGAETQ QSKVAPSSAA SRPVLSSRSD
QSQKNEVFLD VVERLSVLIA SNGSLLKVDV QGEIRLKSFL PSGSEMRIGL TEEFCVGKSE
LRGYGPGIRV DEVSFHSSVN LDEFESHRIL RLQPPQGELT VMRYQLSDDL PSPLPFRLFP
SVQWDRGSGR LQVYLKLRCD LLSKSQALNV RLHLPLPRGV VSLSQELSSP EQKAELAEGA
LRWDLPRVQG GSQLSGLFQM DVPGPPGPPS HGLSTSASPL GLGPASLSFE LPRHTCSGLQ
VRFLRLAFRP CGNANPHKWV RHLSHSDAYV IRI
