LRRK2_MOUSE
ID LRRK2_MOUSE Reviewed; 2527 AA.
AC Q5S006; E9QNJ2; Q8BWG7; Q8BZJ6; Q8CI84; Q8K062;
DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Leucine-rich repeat serine/threonine-protein kinase 2;
DE EC=2.7.11.1 {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462};
DE EC=3.6.5.- {ECO:0000250|UniProtKB:Q5S007};
GN Name=Lrrk2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Swiss Webster; TISSUE=Embryo;
RX PubMed=15541309; DOI=10.1016/j.neuron.2004.11.005;
RA Zimprich A., Biskup S., Leitner P., Lichtner P., Farrer M., Lincoln S.J.,
RA Kachergus J.M., Hulihan M.M., Uitti R.J., Calne D.B., Stoessl A.J.,
RA Pfeiffer R.F., Patenge N., Carballo Carbajal I., Vieregge P., Asmus F.,
RA Mueller-Myhsok B., Dickson D.W., Meitinger T., Strom T.M., Wszolek Z.K.,
RA Gasser T.;
RT "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic
RT pathology.";
RL Neuron 44:601-607(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-946 AND 1162-1707.
RC STRAIN=C57BL/6J; TISSUE=Kidney;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1688-2527.
RC STRAIN=FVB/N; TISSUE=Kidney;
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 [5]
RP TISSUE SPECIFICITY.
RX PubMed=16532471; DOI=10.1002/ana.20808;
RA Galter D., Westerlund M., Carmine A., Lindqvist E., Sydow O., Olson L.;
RT "LRRK2 expression linked to dopamine-innervated areas.";
RL Ann. Neurol. 59:714-719(2006).
RN [6]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17120249; DOI=10.1002/ana.21019;
RA Biskup S., Moore D.J., Celsi F., Higashi S., West A.B., Andrabi S.A.,
RA Kurkinen K., Yu S.W., Savitt J.M., Waldvogel H.J., Faull R.L., Emson P.C.,
RA Torp R., Ottersen O.P., Dawson T.M., Dawson V.L.;
RT "Localization of LRRK2 to membranous and vesicular structures in mammalian
RT brain.";
RL Ann. Neurol. 60:557-569(2006).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=16487147; DOI=10.1111/j.1460-9568.2006.04616.x;
RA Simon-Sanchez J., Herranz-Perez V., Olucha-Bordonau F., Perez-Tur J.;
RT "LRRK2 is expressed in areas affected by Parkinson's disease in the adult
RT mouse brain.";
RL Eur. J. Neurosci. 23:659-666(2006).
RN [8]
RP TISSUE SPECIFICITY.
RX PubMed=16504409; DOI=10.1016/j.neuroscience.2006.01.017;
RA Melrose H., Lincoln S., Tyndall G., Dickson D., Farrer M.;
RT "Anatomical localization of leucine-rich repeat kinase 2 in mouse brain.";
RL Neuroscience 139:791-794(2006).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-935, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [10]
RP INTERACTION WITH VPS35 AND RAB29.
RX PubMed=23395371; DOI=10.1016/j.neuron.2012.11.033;
RA MacLeod D.A., Rhinn H., Kuwahara T., Zolin A., Di Paolo G., McCabe B.D.,
RA MacCabe B.D., Marder K.S., Honig L.S., Clark L.N., Small S.A.,
RA Abeliovich A.;
RT "RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and
RT Parkinson's disease risk.";
RL Neuron 77:425-439(2013).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH SEC16A, AND MUTAGENESIS OF
RP ARG-1441.
RX PubMed=25201882; DOI=10.15252/embj.201487807;
RA Cho H.J., Yu J., Xie C., Rudrabhatla P., Chen X., Wu J., Parisiadou L.,
RA Liu G., Sun L., Ma B., Ding J., Liu Z., Cai H.;
RT "Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow
RT ER-Golgi export.";
RL EMBO J. 33:2314-2331(2014).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PHOSPHORYLATION AT
RP SER-935, AND MUTAGENESIS OF ALA-2016 AND GLY-2019.
RX PubMed=26824392; DOI=10.7554/elife.12813;
RA Steger M., Tonelli F., Ito G., Davies P., Trost M., Vetter M., Wachter S.,
RA Lorentzen E., Duddy G., Wilson S., Baptista M.A., Fiske B.K., Fell M.J.,
RA Morrow J.A., Reith A.D., Alessi D.R., Mann M.;
RT "Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates
RT a subset of Rab GTPases.";
RL Elife 5:0-0(2016).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ARG-1441 AND GLY-2019.
RX PubMed=29125462; DOI=10.7554/elife.31012;
RA Steger M., Diez F., Dhekne H.S., Lis P., Nirujogi R.S., Karayel O.,
RA Tonelli F., Martinez T.N., Lorentzen E., Pfeffer S.R., Alessi D.R.,
RA Mann M.;
RT "Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation
RT establishes a connection to ciliogenesis.";
RL Elife 6:0-0(2017).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH APP,
RP TISSUE SPECIFICITY, AND MUTAGENESIS OF GLY-2019.
RX PubMed=28720718; DOI=10.1126/scisignal.aam6790;
RA Chen Z.C., Zhang W., Chua L.L., Chai C., Li R., Lin L., Cao Z.,
RA Angeles D.C., Stanton L.W., Peng J.H., Zhou Z.D., Lim K.L., Zeng L.,
RA Tan E.K.;
RT "Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD
RT activity and neurotoxicity in Parkinson's disease.";
RL Sci. Signal. 10:0-0(2017).
RN [15]
RP FUNCTION, AND MUTAGENESIS OF ARG-1441.
RX PubMed=30398148; DOI=10.7554/elife.40202;
RA Dhekne H.S., Yanatori I., Gomez R.C., Tonelli F., Diez F., Schuele B.,
RA Steger M., Alessi D.R., Pfeffer S.R.;
RT "A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and
RT Sonic hedgehog signaling in the brain.";
RL Elife 7:0-0(2018).
RN [16]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ARG-1441.
RX PubMed=29212815; DOI=10.15252/embj.201798099;
RA Purlyte E., Dhekne H.S., Sarhan A.R., Gomez R., Lis P., Wightman M.,
RA Martinez T.N., Tonelli F., Pfeffer S.R., Alessi D.R.;
RT "Rab29 activation of the Parkinson's disease-associated LRRK2 kinase.";
RL EMBO J. 37:1-18(2018).
CC -!- FUNCTION: Serine/threonine-protein kinase which phosphorylates a broad
CC range of proteins involved in multiple processes such as neuronal
CC plasticity, autophagy, and vesicle trafficking (PubMed:26824392,
CC PubMed:29125462, PubMed:28720718, PubMed:30398148, PubMed:29212815). Is
CC a key regulator of RAB GTPases by regulating the GTP/GDP exchange and
CC interaction partners of RABs through phosphorylation (PubMed:26824392,
CC PubMed:28720718, PubMed:30398148, PubMed:29212815, PubMed:29125462).
CC Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB8A, RAB8B, RAB10, RAB12,
CC RAB35, and RAB43 (PubMed:26824392, PubMed:28720718, PubMed:30398148,
CC PubMed:29212815). Regulates the RAB3IP-catalyzed GDP/GTP exchange for
CC RAB8A through the phosphorylation of 'Thr-72' on RAB8A (By similarity).
CC Inhibits the interaction between RAB8A and GDI1 and/or GDI2 by
CC phosphorylating 'Thr-72' on RAB8A (By similarity). Regulates primary
CC ciliogenesis through phosphorylation of RAB8A and RAB10, which promotes
CC SHH signaling in the brain (PubMed:29125462, PubMed:30398148). Together
CC with RAB29, plays a role in the retrograde trafficking pathway for
CC recycling proteins, such as mannose-6-phosphate receptor (M6PR),
CC between lysosomes and the Golgi apparatus in a retromer-dependent
CC manner (By similarity). Regulates neuronal process morphology in the
CC intact central nervous system (CNS) (By similarity). Plays an important
CC role in recruiting SEC16A to endoplasmic reticulum exit sites (ERES)
CC and in regulating ER to Golgi vesicle-mediated transport and ERES
CC organization (PubMed:25201882). Positively regulates autophagy through
CC a calcium-dependent activation of the CaMKK/AMPK signaling pathway (By
CC similarity). The process involves activation of nicotinic acid adenine
CC dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and
CC calcium release from lysosomes (By similarity). Phosphorylates PRDX3
CC (By similarity). By phosphorylating APP on 'Thr-743', which promotes
CC the production and the nuclear translocation of the APP intracellular
CC domain (AICD), regulates dopaminergic neuron apoptosis
CC (PubMed:28720718). Independent of its kinase activity, inhibits the
CC proteosomal degradation of MAPT, thus promoting MAPT oligomerization
CC and secretion (By similarity). In addition, has GTPase activity via its
CC Roc domain which regulates LRKK2 kinase activity (By similarity).
CC {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:25201882,
CC ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718,
CC ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815,
CC ECO:0000269|PubMed:30398148}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:26824392,
CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718,
CC ECO:0000269|PubMed:29125462};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189;
CC Evidence={ECO:0000250|UniProtKB:Q5S007};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q5S007};
CC -!- ACTIVITY REGULATION: Kinase activity is regulated by the GTPase
CC activity of the ROC domain (Probable). GTP-bound LLRK2 kinase activity
CC is stimulated by RAB29 (Probable). Inhibited by small molecule
CC inhibitors MLi-2 and LRRK2-IN-1 (PubMed:26824392, PubMed:28720718).
CC {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718,
CC ECO:0000305|PubMed:29212815}.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with PRKN, PRDX3 and
CC TPCN2 (By similarity). Interacts with VPS35 and RAB29
CC (PubMed:23395371). Interacts (via ROC domain) with SEC16A
CC (PubMed:25201882). Interacts with APP; interaction promotes
CC phosphorylation of 'Thr-743' of APP (PubMed:28720718). Interacts with
CC MAPT (By similarity). Interacts with RAB8A, RAB10, and RAB12 (By
CC similarity). Interacts with YWHAG; this interaction is dependent on
CC phosphorylation of Ser-910 and either Ser-935 or Ser-1444 (By
CC similarity). Interacts with SFN; this interaction is dependent on
CC phosphorylation of Ser-910 and/or Ser-935 (By similarity).
CC {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:23395371,
CC ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:28720718}.
CC -!- INTERACTION:
CC Q5S006; Q9EPJ9: Arfgap1; NbExp=3; IntAct=EBI-2693710, EBI-6288020;
CC Q5S006; O55143: Atp2a2; NbExp=9; IntAct=EBI-2693710, EBI-770763;
CC Q5S006; Q8K1M6: Dnm1l; NbExp=5; IntAct=EBI-2693710, EBI-2365792;
CC Q5S006; Q5S006: Lrrk2; NbExp=6; IntAct=EBI-2693710, EBI-2693710;
CC Q5S006; P46460: Nsf; NbExp=3; IntAct=EBI-2693710, EBI-398006;
CC Q5S006; P31324: Prkar2b; NbExp=3; IntAct=EBI-2693710, EBI-455340;
CC Q5S006; Q9CQV8: Ywhab; NbExp=6; IntAct=EBI-2693710, EBI-771608;
CC Q5S006; P62259: Ywhae; NbExp=4; IntAct=EBI-2693710, EBI-356480;
CC Q5S006; P61982: Ywhag; NbExp=10; IntAct=EBI-2693710, EBI-359843;
CC Q5S006; P68510: Ywhah; NbExp=7; IntAct=EBI-2693710, EBI-444641;
CC Q5S006; P68254: Ywhaq; NbExp=4; IntAct=EBI-2693710, EBI-400675;
CC Q5S006; P63101: Ywhaz; NbExp=5; IntAct=EBI-2693710, EBI-354751;
CC Q5S006; P26038: MSN; Xeno; NbExp=2; IntAct=EBI-2693710, EBI-528768;
CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle
CC {ECO:0000250|UniProtKB:Q5S007}. Perikaryon
CC {ECO:0000250|UniProtKB:Q5S007}. Cell projection, axon
CC {ECO:0000250|UniProtKB:Q5S007}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:Q5S007}. Golgi apparatus membrane
CC {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29212815}; Peripheral
CC membrane protein {ECO:0000269|PubMed:17120249,
CC ECO:0000269|PubMed:29212815}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:25201882}; Peripheral
CC membrane protein {ECO:0000269|PubMed:17120249,
CC ECO:0000269|PubMed:25201882}. Cytoplasmic vesicle, secretory vesicle,
CC synaptic vesicle membrane {ECO:0000269|PubMed:17120249}. Endosome
CC {ECO:0000269|PubMed:17120249}. Lysosome {ECO:0000269|PubMed:17120249}.
CC Mitochondrion outer membrane {ECO:0000269|PubMed:17120249}; Peripheral
CC membrane protein {ECO:0000269|PubMed:17120249}. Note=Colocalized with
CC RAB29 along tubular structures emerging from Golgi apparatus (By
CC similarity). Localizes to endoplasmic reticulum exit sites (ERES), also
CC known as transitional endoplasmic reticulum (tER) (PubMed:25201882).
CC {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:25201882}.
CC -!- TISSUE SPECIFICITY: Expressed in the brain (at protein level)
CC (PubMed:28720718). Detected throughout the adult brain. Expressed in
CC deep cerebral cortex layers, superficial cingulate cortex layers, the
CC piriform cortex, hippocampal formation, caudate putamen, substantia
CC nigra, the basolateral and basomedial anterior amygdala nuclei,
CC reticular thalamic nucleus and also in the cerebellar granular cell
CC layer. Highly expressed in the striatum, cortex and olfactory tubercle.
CC Little or no expression in the substantia nigra, where dopaminergic
CC neurons preferentially degenerate in Parkinson disease. Expression is
CC particularly high in brain dopaminoceptive areas. High and strikingly
CC specific expression in striatum and parts of cortex and no signals in
CC dopamine neurons. {ECO:0000269|PubMed:16487147,
CC ECO:0000269|PubMed:16504409, ECO:0000269|PubMed:16532471,
CC ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:28720718}.
CC -!- DOMAIN: The seven-bladed WD repeat region is critical for synaptic
CC vesicle trafficking and mediates interaction with multiple vesicle-
CC associated presynaptic proteins (By similarity). It also mediates
CC homodimerization and regulates kinase activity (By similarity).
CC {ECO:0000250|UniProtKB:Q5S007}.
CC -!- DOMAIN: The Roc domain mediates homodimerization and regulates kinase
CC activity. {ECO:0000250|UniProtKB:Q5S007}.
CC -!- PTM: Autophosphorylated (PubMed:28720718, PubMed:29212815).
CC Phosphorylation of Ser-910 and Ser-935 or Ser-1444 facilitates
CC interaction with YWHAG (By similarity). Phosphorylation of Ser-910
CC and/or Ser-935 facilitates interaction with SFN (By similarity).
CC {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:28720718,
CC ECO:0000269|PubMed:29212815}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. {ECO:0000305}.
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DR EMBL; AY792512; AAV63976.1; -; mRNA.
DR EMBL; AC099704; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC158752; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AK052591; BAC35052.1; -; mRNA.
DR EMBL; AK034413; BAC28700.1; -; mRNA.
DR EMBL; BC034074; AAH34074.1; -; mRNA.
DR EMBL; BC035949; AAH35949.1; -; mRNA.
DR CCDS; CCDS37180.1; -.
DR RefSeq; NP_080006.3; NM_025730.3.
DR AlphaFoldDB; Q5S006; -.
DR SMR; Q5S006; -.
DR BioGRID; 211674; 42.
DR DIP; DIP-58648N; -.
DR IntAct; Q5S006; 76.
DR STRING; 10090.ENSMUSP00000052584; -.
DR ChEMBL; CHEMBL2010622; -.
DR iPTMnet; Q5S006; -.
DR PhosphoSitePlus; Q5S006; -.
DR jPOST; Q5S006; -.
DR MaxQB; Q5S006; -.
DR PaxDb; Q5S006; -.
DR PeptideAtlas; Q5S006; -.
DR PRIDE; Q5S006; -.
DR ProteomicsDB; 292371; -.
DR ABCD; Q5S006; 1 sequenced antibody.
DR Antibodypedia; 2109; 912 antibodies from 48 providers.
DR DNASU; 66725; -.
DR Ensembl; ENSMUST00000060642; ENSMUSP00000052584; ENSMUSG00000036273.
DR GeneID; 66725; -.
DR KEGG; mmu:66725; -.
DR UCSC; uc007xhz.1; mouse.
DR CTD; 120892; -.
DR MGI; MGI:1913975; Lrrk2.
DR VEuPathDB; HostDB:ENSMUSG00000036273; -.
DR eggNOG; KOG0192; Eukaryota.
DR eggNOG; KOG0619; Eukaryota.
DR GeneTree; ENSGT00940000158267; -.
DR HOGENOM; CLU_000815_0_0_1; -.
DR InParanoid; Q5S006; -.
DR OMA; WEVLGIH; -.
DR OrthoDB; 14978at2759; -.
DR PhylomeDB; Q5S006; -.
DR TreeFam; TF313679; -.
DR Reactome; R-MMU-8857538; PTK6 promotes HIF1A stabilization.
DR BioGRID-ORCS; 66725; 3 hits in 75 CRISPR screens.
DR ChiTaRS; Lrrk2; mouse.
DR PRO; PR:Q5S006; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; Q5S006; protein.
DR Bgee; ENSMUSG00000036273; Expressed in granulocyte and 154 other tissues.
DR Genevisible; Q5S006; MM.
DR GO; GO:0044753; C:amphisome; ISO:MGI.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0044754; C:autolysosome; ISO:MGI.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0099400; C:caveola neck; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0032473; C:cytoplasmic side of mitochondrial outer membrane; ISO:MGI.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0030425; C:dendrite; IDA:ParkinsonsUK-UCL.
DR GO; GO:0032839; C:dendrite cytoplasm; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0070971; C:endoplasmic reticulum exit site; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005798; C:Golgi-associated vesicle; ISO:MGI.
DR GO; GO:0030426; C:growth cone; ISO:MGI.
DR GO; GO:0016234; C:inclusion body; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; ISO:MGI.
DR GO; GO:0045121; C:membrane raft; IDA:MGI.
DR GO; GO:0005902; C:microvillus; ISO:MGI.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB.
DR GO; GO:0031966; C:mitochondrial membrane; ISO:MGI.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0097487; C:multivesicular body, internal vesicle; ISO:MGI.
DR GO; GO:0043005; C:neuron projection; ISO:MGI.
DR GO; GO:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0043204; C:perikaryon; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0098794; C:postsynapse; IEA:GOC.
DR GO; GO:0099523; C:presynaptic cytosol; IDA:SynGO.
DR GO; GO:1990904; C:ribonucleoprotein complex; IDA:MGI.
DR GO; GO:0045202; C:synapse; IDA:MGI.
DR GO; GO:0008021; C:synaptic vesicle; IDA:MGI.
DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043195; C:terminal bouton; IC:ParkinsonsUK-UCL.
DR GO; GO:0005802; C:trans-Golgi network; IDA:MGI.
DR GO; GO:1990909; C:Wnt signalosome; IDA:ParkinsonsUK-UCL.
DR GO; GO:0003779; F:actin binding; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:1904713; F:beta-catenin destruction complex binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0030276; F:clathrin binding; ISO:MGI.
DR GO; GO:0005525; F:GTP binding; ISO:MGI.
DR GO; GO:0034211; F:GTP-dependent protein kinase activity; ISO:MGI.
DR GO; GO:0005096; F:GTPase activator activity; ISO:MGI.
DR GO; GO:0003924; F:GTPase activity; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004706; F:JUN kinase kinase kinase activity; ISO:MGI.
DR GO; GO:0016301; F:kinase activity; ISS:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; ISO:MGI.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; ISO:MGI.
DR GO; GO:0036479; F:peroxidase inhibitor activity; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR GO; GO:0051018; F:protein kinase A binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:MGI.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IBA:GO_Central.
DR GO; GO:0044877; F:protein-containing complex binding; IC:ParkinsonsUK-UCL.
DR GO; GO:0030159; F:signaling receptor complex adaptor activity; IC:ParkinsonsUK-UCL.
DR GO; GO:0031267; F:small GTPase binding; IPI:BHF-UCL.
DR GO; GO:0000149; F:SNARE binding; ISO:MGI.
DR GO; GO:0017075; F:syntaxin-1 binding; ISO:MGI.
DR GO; GO:0044325; F:transmembrane transporter binding; ISO:MGI.
DR GO; GO:0015631; F:tubulin binding; ISO:MGI.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0019722; P:calcium-mediated signaling; ISO:MGI.
DR GO; GO:1903351; P:cellular response to dopamine; ISO:MGI.
DR GO; GO:0071287; P:cellular response to manganese ion; ISO:MGI.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IBA:GO_Central.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISO:MGI.
DR GO; GO:0009267; P:cellular response to starvation; ISO:MGI.
DR GO; GO:0008340; P:determination of adult lifespan; ISO:MGI.
DR GO; GO:0006897; P:endocytosis; ISO:MGI.
DR GO; GO:0007029; P:endoplasmic reticulum organization; IMP:UniProtKB.
DR GO; GO:0060079; P:excitatory postsynaptic potential; IMP:ParkinsonsUK-UCL.
DR GO; GO:0035640; P:exploration behavior; ISO:MGI.
DR GO; GO:0007030; P:Golgi organization; IGI:MGI.
DR GO; GO:0046039; P:GTP metabolic process; ISO:MGI.
DR GO; GO:0048312; P:intracellular distribution of mitochondria; ISO:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; IMP:ParkinsonsUK-UCL.
DR GO; GO:0007254; P:JNK cascade; ISO:MGI.
DR GO; GO:0035641; P:locomotory exploration behavior; IMP:ParkinsonsUK-UCL.
DR GO; GO:0007040; P:lysosome organization; ISO:MGI.
DR GO; GO:0000165; P:MAPK cascade; ISO:MGI.
DR GO; GO:0051646; P:mitochondrion localization; ISO:MGI.
DR GO; GO:0007005; P:mitochondrion organization; ISO:MGI.
DR GO; GO:1902902; P:negative regulation of autophagosome assembly; ISO:MGI.
DR GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:0090394; P:negative regulation of excitatory postsynaptic potential; IMP:ParkinsonsUK-UCL.
DR GO; GO:0034260; P:negative regulation of GTPase activity; ISO:MGI.
DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; ISO:MGI.
DR GO; GO:0016242; P:negative regulation of macroautophagy; ISO:MGI.
DR GO; GO:1901215; P:negative regulation of neuron death; ISO:MGI.
DR GO; GO:0010977; P:negative regulation of neuron projection development; ISO:MGI.
DR GO; GO:0032091; P:negative regulation of protein binding; ISO:MGI.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010955; P:negative regulation of protein processing; ISO:MGI.
DR GO; GO:1903215; P:negative regulation of protein targeting to mitochondrion; ISO:MGI.
DR GO; GO:1903125; P:negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation; ISO:MGI.
DR GO; GO:0007528; P:neuromuscular junction development; ISO:MGI.
DR GO; GO:0070997; P:neuron death; ISO:MGI.
DR GO; GO:0140058; P:neuron projection arborization; ISO:MGI.
DR GO; GO:0048812; P:neuron projection morphogenesis; ISS:UniProtKB.
DR GO; GO:0021772; P:olfactory bulb development; ISO:MGI.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:MGI.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISO:MGI.
DR GO; GO:0016310; P:phosphorylation; ISO:MGI.
DR GO; GO:0010508; P:positive regulation of autophagy; IMP:BHF-UCL.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; ISS:ParkinsonsUK-UCL.
DR GO; GO:0060161; P:positive regulation of dopamine receptor signaling pathway; ISO:MGI.
DR GO; GO:1901727; P:positive regulation of histone deacetylase activity; IMP:MGI.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISO:MGI.
DR GO; GO:1903980; P:positive regulation of microglial cell activation; ISO:MGI.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISO:MGI.
DR GO; GO:0043068; P:positive regulation of programmed cell death; ISO:MGI.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:BHF-UCL.
DR GO; GO:1902499; P:positive regulation of protein autoubiquitination; ISO:MGI.
DR GO; GO:0032092; P:positive regulation of protein binding; ISO:MGI.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; ISO:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISO:MGI.
DR GO; GO:1900244; P:positive regulation of synaptic vesicle endocytosis; ISO:MGI.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISO:MGI.
DR GO; GO:0046777; P:protein autophosphorylation; ISO:MGI.
DR GO; GO:0006606; P:protein import into nucleus; IDA:MGI.
DR GO; GO:0008104; P:protein localization; IMP:ParkinsonsUK-UCL.
DR GO; GO:0070973; P:protein localization to endoplasmic reticulum exit site; IMP:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; ISO:MGI.
DR GO; GO:0010506; P:regulation of autophagy; ISO:MGI.
DR GO; GO:2000172; P:regulation of branching morphogenesis of a nerve; ISO:MGI.
DR GO; GO:1905289; P:regulation of CAMKK-AMPK signaling cascade; ISO:MGI.
DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; IPI:ParkinsonsUK-UCL.
DR GO; GO:0061001; P:regulation of dendritic spine morphogenesis; IGI:ParkinsonsUK-UCL.
DR GO; GO:0060159; P:regulation of dopamine receptor signaling pathway; IMP:ParkinsonsUK-UCL.
DR GO; GO:0060628; P:regulation of ER to Golgi vesicle-mediated transport; IMP:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:0035564; P:regulation of kidney size; IMP:BHF-UCL.
DR GO; GO:0040012; P:regulation of locomotion; ISO:MGI.
DR GO; GO:0035751; P:regulation of lysosomal lumen pH; ISO:MGI.
DR GO; GO:0042391; P:regulation of membrane potential; ISO:MGI.
DR GO; GO:0051900; P:regulation of mitochondrial depolarization; ISO:MGI.
DR GO; GO:1902692; P:regulation of neuroblast proliferation; ISO:MGI.
DR GO; GO:1901214; P:regulation of neuron death; ISO:MGI.
DR GO; GO:0014041; P:regulation of neuron maturation; ISO:MGI.
DR GO; GO:0010738; P:regulation of protein kinase A signaling; IMP:ParkinsonsUK-UCL.
DR GO; GO:0031647; P:regulation of protein stability; ISO:MGI.
DR GO; GO:1905279; P:regulation of retrograde transport, endosome to Golgi; ISO:MGI.
DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IMP:ParkinsonsUK-UCL.
DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IDA:SynGO.
DR GO; GO:2000300; P:regulation of synaptic vesicle exocytosis; ISO:MGI.
DR GO; GO:1902803; P:regulation of synaptic vesicle transport; IMP:ParkinsonsUK-UCL.
DR GO; GO:0006979; P:response to oxidative stress; ISO:MGI.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR GO; GO:0021756; P:striatum development; IEA:Ensembl.
DR GO; GO:0036465; P:synaptic vesicle recycling; TAS:ParkinsonsUK-UCL.
DR GO; GO:0022028; P:tangential migration from the subventricular zone to the olfactory bulb; ISO:MGI.
DR GO; GO:1904887; P:Wnt signalosome assembly; ISO:MGI.
DR Gene3D; 1.25.10.10; -; 2.
DR Gene3D; 1.25.40.20; -; 1.
DR Gene3D; 2.130.10.10; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR Gene3D; 3.80.10.10; -; 2.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR032171; COR.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR025875; Leu-rich_rpt_4.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR020859; ROC_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR InterPro; IPR036322; WD40_repeat_dom_sf.
DR Pfam; PF16095; COR; 1.
DR Pfam; PF12799; LRR_4; 1.
DR Pfam; PF13855; LRR_8; 2.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00369; LRR_TYP; 7.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF48371; SSF48371; 2.
DR SUPFAM; SSF48403; SSF48403; 1.
DR SUPFAM; SSF50978; SSF50978; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51450; LRR; 11.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS51424; ROC; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Autophagy; Cell projection; Coiled coil; Cytoplasmic vesicle;
KW Differentiation; Endoplasmic reticulum; Endosome; Golgi apparatus;
KW GTP-binding; GTPase activation; Hydrolase; Kinase; Leucine-rich repeat;
KW Lysosome; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; Synapse; Transferase; WD repeat.
FT CHAIN 1..2527
FT /note="Leucine-rich repeat serine/threonine-protein kinase
FT 2"
FT /id="PRO_0000086239"
FT REPEAT 983..1004
FT /note="LRR 1"
FT REPEAT 1012..1033
FT /note="LRR 2"
FT REPEAT 1036..1057
FT /note="LRR 3"
FT REPEAT 1059..1080
FT /note="LRR 4"
FT REPEAT 1084..1105
FT /note="LRR 5"
FT REPEAT 1108..1129
FT /note="LRR 6"
FT REPEAT 1130..1151
FT /note="LRR 7"
FT REPEAT 1174..1195
FT /note="LRR 8"
FT REPEAT 1197..1218
FT /note="LRR 9"
FT REPEAT 1221..1242
FT /note="LRR 10"
FT REPEAT 1246..1267
FT /note="LRR 11"
FT REPEAT 1269..1291
FT /note="LRR 12"
FT DOMAIN 1328..1511
FT /note="Roc"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758"
FT DOMAIN 1879..2146
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REPEAT 2139..2183
FT /note="WD 1"
FT REPEAT 2188..2228
FT /note="WD 2"
FT REPEAT 2233..2276
FT /note="WD 3"
FT REPEAT 2281..2327
FT /note="WD 4"
FT REPEAT 2333..2377
FT /note="WD 5"
FT REPEAT 2402..2438
FT /note="WD 6"
FT REPEAT 2443..2497
FT /note="WD 7"
FT REGION 957..979
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 9..33
FT /evidence="ECO:0000255"
FT COMPBIAS 958..979
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 1994
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 1341..1348
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758"
FT BINDING 1885..1893
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1906
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 2098..2121
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758"
FT BINDING 2295..2298
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758"
FT MOD_RES 910
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5S007"
FT MOD_RES 935
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:26824392,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 955
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5S007"
FT MOD_RES 973
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5S007"
FT MOD_RES 1292
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5S007"
FT MOD_RES 1444
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5S007"
FT MUTAGEN 1441
FT /note="R->C: Impaired ability to recruit SEC61A and SEC31A
FT to endoplasmic reticulum exit sites. Impaired ability to
FT regulate ER to Golgi vesicle-mediated transport."
FT /evidence="ECO:0000269|PubMed:25201882"
FT MUTAGEN 1441
FT /note="R->G: Increases kinase activity. Reduces primary
FT ciliogenesis. Causes fragmentation of the trans-Golgi
FT network."
FT /evidence="ECO:0000269|PubMed:29125462,
FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148"
FT MUTAGEN 2016
FT /note="A->T: Does not affect kinase activity and decreases
FT sensitivity towards small molecule kinase inhibitors."
FT /evidence="ECO:0000269|PubMed:26824392"
FT MUTAGEN 2019
FT /note="G->S: Increases kinase activity. Causes loss of
FT dopaminergic neurons in the substantia nigra of 20-month
FT old mice due to increased phosphorylation of APP. Reduces
FT primary ciliogenesis."
FT /evidence="ECO:0000269|PubMed:26824392,
FT ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462"
FT CONFLICT 343
FT /note="E -> K (in Ref. 3; BAC35052)"
FT /evidence="ECO:0000305"
FT CONFLICT 777
FT /note="V -> I (in Ref. 1; AAV63976)"
FT /evidence="ECO:0000305"
FT CONFLICT 863
FT /note="K -> N (in Ref. 1; AAV63976)"
FT /evidence="ECO:0000305"
FT CONFLICT 925
FT /note="C -> Y (in Ref. 1; AAV63976)"
FT /evidence="ECO:0000305"
FT CONFLICT 1705..1707
FT /note="WSR -> GQD (in Ref. 3; BAC28700)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 2527 AA; 284732 MW; 706E25C173E36F98 CRC64;
MASGACQGCE EEEEEEALKK LIVRLNNVQE GKQIETLLQL LEDMLVFTYS DRASKLFEDK
NFHVPLLIVL DSYMRVASVQ QAGWSLLCKL IEVCPGTLQS LIGPQDIGND WEVLGIHRLI
LKMLTVHHAN VNLSIVGLKA LDLLLDSGKL TLLILDEECD IFLLIFDAMH RYSANDEVQK
LGCKALHVLF ERVSEEQLTE FVENKDYTIL LSTFGSFRRD KEIVYHVLCC LHSLAVTCSN
VEVLMSGNVR CYNLVVEAMK AFPTNENIQE VSCSLFQKLT LGNFFNILVL NEVHVFVVKA
VRQYPENAAL QISALSCLAL LTETIFLNQD LEERSETQEQ SEEEDSEKLF WLEPCYKALV
RHRKDKHVQE AACWALNNLL MYQNSLHEKI GDEDGQFPAH REVMLSMLMH SSSKDVFQAA
AHALSTLLEQ NVNFRKILLA KGVYLNVLEL MQKHAHAPEV AESGCKMLSH LFEGSNPSLD
TMAAVVPKIL TVMKAHGTSL SVQLEALRAI LHFVVPGLLE ESREDSQCRP NVLRKQCFRT
DIHKLVLVAL NRFIGNPGIQ KCGLKVISSL AHLPDATETL SLQGAVDSVL HTLQMYPDDQ
EIQCLGLHLM GCLMTKKNFC IGTGHLLAKI LASTLQRFKD VAEVQTTGLQ TTLSILELSV
SFSKLLVHYS FDVVIFHQMS SSVVEQKDEQ FLNLCCKCFA KVAVDDELKN TMLERACDQN
NSIMVECLLL LGADANQVKG ATSLIYQVCE KESSPKLVEL LLNGGCREQD VRKALTVSIQ
KGDSQVISLL LRKLALDLAN NSICLGGFGI GKIDPSWLGP LFPDKSSNLR KQTNTGSVLA
RKVLRYQMRN TLQEGVASGS DGKFSEDALA KFGEWTFIPD SSMDSVFGQS DDLDSEGSES
SFLVKRKSNS ISVGEVYRDL ALQRCSPNAQ RHSNSLGPVF DHEDLLRRKR KILSSDESLR
SSRLPSHMRQ SDSSSSLASE REHITSLDLS ANELKDIDAL SQKCCLSSHL EHLTKLELHQ
NSLTSFPQQL CETLKCLIHL DLHSNKFTSF PSFVLKMPRI TNLDASRNDI GPTVVLDPAM
KCPSLKQLNL SYNQLSSIPE NLAQVVEKLE QLLLEGNKIS GICSPLSLKE LKILNLSKNH
IPSLPGDFLE ACSKVESFSA RMNFLAAMPA LPSSITSLKL SQNSFTCIPE AIFSLPHLRS
LDMSHNNIEC LPGPAHWKSL NLRELIFSKN QISTLDFSEN PHVWSRVEKL HLSHNKLKEI
PPEIGCLENL TSLDVSYNLE LRSFPNEMGK LSKIWDLPLD GLHLNFDFKH VGCKAKDIIR
FLQQRLKKAV PYNRMKLMIV GNTGSGKTTL LQQLMKMKKP ELGMQGATVG IDVRDWSIQI
RGKRRKDLVL NVWDFAGREE FYSTHPHFMT QRALYLAVYD LSKGQAEVDA MKPWLFNIKA
RASSSPVILV GTHLDVSDEK QRKACISKIT KELLNKRGFP TIRDYHFVNA TEESDALAKL
RKTIINESLN FKIRDQPVVG QLIPDCYVEL EKIILSERKA VPTEFPVINR KHLLQLVNEH
QLQLDENELP HAVHFLNESG VLLHFQDPAL QLSDLYFVEP KWLCKVMAQI LTVKVDGCLK
HPKGIISRRD VEKFLSKKKR FPKNYMMQYF KLLEKFQIAL PIGEEYLLVP SSLSDHRPVI
ELPHCENSEI IIRLYEMPYF PMGFWSRLIN RLLEISPFML SGRERALRPN RMYWRQGIYL
NWSPEAYCLV GSEVLDNRPE SFLKITVPSC RKGCILLGRV VDHIDSLMEE WFPGLLEIDI
CGEGETLLKK WALYSFNDGE EHQKILLDEL MKKAEEGDLL INPDQPRLTI PISQIAPDLI
LADLPRNIML NNDELEFEEA PEFLLGDGSF GSVYRAAYEG EEVAVKIFNK HTSLRLLRQE
LVVLCHLHHP SLISLLAAGI RPRMLVMELA SKGSLDRLLQ QDKASLTRTL QHRIALHVAD
GLRYLHSAMI IYRDLKPHNV LLFTLYPNAA IIAKIADYGI AQYCCRMGIK TSEGTPGFRA
PEVARGNVIY NQQADVYSFG LLLHDIWTTG SRIMEGLRFP NEFDELAIQG KLPDPVKEYG
CAPWPMVEKL ITKCLKENPQ ERPTSAQVFD ILNSAELICL MRHILIPKNI IVECMVATNL
NSKSATLWLG CGNTEKGQLS LFDLNTERYS YEEVADSRIL CLALVHLAAE KESWVVCGTQ
SGALLVINVE EETKRHTLEK MTDSVTCLHC NSLAKQSKQS NFLLVGTADG NLMIFEDKAV
KCKGAAPLKT LHIGDVSTPL MCLSESLNSS ERHITWGGCG TKVFSFSNDF TIQKLIETKT
NQLFSYAAFS DSNIIALAVD TALYIAKKNS PVVEVWDKKT EKLCELIDCV HFLKEVMVKL
NKESKHQLSY SGRVKALCLQ KNTALWIGTG GGHILLLDLS TRRVIRTIHN FCDSVRAMAT
AQLGSLKNVM LVLGYKRKST EGIQEQKEIQ SCLSIWDLNL PHEVQNLEKH IEVRTELADK
MRKTSVE
