Lrrk2
entrez
66725
canonical
uniprot
Q5S006
canonical
ensembl
ENSMUSG00000036273
resolver
ensp
ENSMUSP00000052584
resolver
ensp
ENSMUSP00000190082
resolver
enst
ENSMUST00000060642
resolver
genesymbol
Lrrk2
resolver
uniprot
E9QNJ2
resolver
uniprot
Q8BWG7
resolver
uniprot
Q8BZJ6
resolver
uniprot
Q8CI84
resolver
uniprot
Q8K062
resolver
uniprot
Q9CQG8
resolver
uniprot_entry
LRRK2_MOUSE
resolver
uniprot_entry
Q9CQG8_MOUSE
resolver
uniprot_sec
E9QNJ2
resolver
uniprot_sec
Q8BWG7
resolver
uniprot_sec
Q8BZJ6
resolver
uniprot_sec
Q8CI84
resolver
uniprot_sec
Q8K062
resolver
activity_regulation
ACTIVITY REGULATION: Kinase activity is regulated by the GTPase activity of the ROC domain (By similarity). GTP-bound LRRK2 kinase activity is stimulated by RAB29 (By similarity). Phosphorylation of RAB10 'Thr-73' is stimulated by RAB29 and RAB32 (By similarity). Inhibited by small molecule inhibitors MLi-2 and LRRK2-IN-1 (PubMed:26824392, PubMed:28720718). {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000305|PubMed:29212815}.
uniprot
proteins
amino_acid_sequence
MASGACQGCEEEEEEEALKKLIVRLNNVQEGKQIETLLQLLEDMLVFTYSDRASKLFEDKNFHVPLLIVLDSYMRVASVQQAGWSLLCKLIEVCPGTLQSLIGPQDIGNDWEVLGIHRLILKMLTVHHANVNLSIVGLKALDLLLDSGKLTLLILDEECDIFLLIFDAMHRYSANDEVQKLGCKALHVLFERVSEEQLTEFVENKDYTILLSTFGSFRRDKEIVYHVLCCLHSLAVTCSNVEVLMSGNVRCYNLVVEAMKAFPTNENIQEVSCSLFQKLTLGNFFNILVLNEVHVFVVKAVRQYPENAALQISALSCLALLTETIFLNQDLEERSETQEQSEEEDSEKLFWLEPCYKALVRHRKDKHVQEAACWALNNLLMYQNSLHEKIGDEDGQFPAHREVMLSMLMHSSSKDVFQAAAHALSTLLEQNVNFRKILLAKGVYLNVLELMQKHAHAPEVAESGCKMLSHLFEGSNPSLDTMAAVVPKILTVMKAHGTSLSVQLEALRAILHFVVPGLLEESREDSQCRPNVLRKQCFRTDIHKLVLVALNRFIGNPGIQKCGLKVISSLAHLPDATETLSLQGAVDSVLHTLQMYPDDQEIQCLGLHLMGCLMTKKNFCIGTGHLLAKILASTLQRFKDVAEVQTTGLQTTLSILELSVSFSKLLVHYSFDVVIFHQMSSSVVEQKDEQFLNLCCKCFAKVAVDDELKNTMLERACDQNNSIMVECLLLLGADANQVKGATSLIYQVCEKESSPKLVELLLNGGCREQDVRKALTVSIQKGDSQVISLLLRKLALDLANNSICLGGFGIGKIDPSWLGPLFPDKSSNLRKQTNTGSVLARKVLRYQMRNTLQEGVASGSDGKFSEDALAKFGEWTFIPDSSMDSVFGQSDDLDSEGSESSFLVKRKSNSISVGEVYRDLALQRCSPNAQRHSNSLGPVFDHEDLLRRKRKILSSDESLRSSRLPSHMRQSDSSSSLASEREHITSLDLSANELKDIDALSQKCCLSSHLEHLTKLELHQNSLTSFPQQLCETLKCLIHLDLHSNKFTSFPSFVLKMPRITNLDASRNDIGPTVVLDPAMKCPSLKQLNLSYNQLSSIPENLAQVVEKLEQLLLEGNKISGICSPLSLKELKILNLSKNHIPSLPGDFLEACSKVESFSARMNFLAAMPALPSSITSLKLSQNSFTCIPEAIFSLPHLRSLDMSHNNIECLPGPAHWKSLNLRELIFSKNQISTLDFSENPHVWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDGLHLNFDFKHVGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKMKKPELGMQGATVGIDVRDWSIQIRGKRRKDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACISKITKELLNKRGFPTIRDYHFVNATEESDALAKLRKTIINESLNFKIRDQPVVGQLIPDCYVELEKIILSERKAVPTEFPVINRKHLLQLVNEHQLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKVMAQILTVKVDGCLKHPKGIISRRDVEKFLSKKKRFPKNYMMQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPFMLSGRERALRPNRMYWRQGIYLNWSPEAYCLVGSEVLDNRPESFLKITVPSCRKGCILLGRVVDHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDELMKKAEEGDLLINPDQPRLTIPISQIAPDLILADLPRNIMLNNDELEFEEAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRAPEVARGNVIYNQQADVYSFGLLLHDIWTTGSRIMEGLRFPNEFDELAIQGKLPDPVKEYGCAPWPMVEKLITKCLKENPQERPTSAQVFDILNSAELICLMRHILIPKNIIVECMVATNLNSKSATLWLGCGNTEKGQLSLFDLNTERYSYEEVADSRILCLALVHLAAEKESWVVCGTQSGALLVINVEEETKRHTLEKMTDSVTCLHCNSLAKQSKQSNFLLVGTADGNLMIFEDKAVKCKGAAPLKTLHIGDVSTPLMCLSESLNSSERHITWGGCGTKVFSFSNDFTIQKLIETKTNQLFSYAAFSDSNIIALAVDTALYIAKKNSPVVEVWDKKTEKLCELIDCVHFLKEVMVKLNKESKHQLSYSGRVKALCLQKNTALWIGTGGGHILLLDLSTRRVIRTIHNFCDSVRAMATAQLGSLKNVMLVLGYKRKSTEGIQEQKEIQSCLSIWDLNLPHEVQNLEKHIEVRTELADKMRKTSVE
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
ec_number
3.6.5.-
uniprot
proteins
function
FUNCTION: Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking (PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29212815, PubMed:30398148). Is a key regulator of RAB GTPases by regulating the GTP/GDP exchange and interaction partners of RABs through phosphorylation (PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29212815, PubMed:30398148). Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB8A, RAB8B, RAB10, RAB12, RAB29, RAB35, and RAB43 (PubMed:26824392, PubMed:28720718, PubMed:29212815, PubMed:30398148). Regulates the RAB3IP-catalyzed GDP/GTP exchange for RAB8A through the phosphorylation of 'Thr-72' on RAB8A (By similarity). Inhibits the interaction between RAB8A and GDI1 and/or GDI2 by phosphorylating 'Thr-72' on RAB8A (By similarity). Regulates primary ciliogenesis through phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the brain (PubMed:29125462, PubMed:30398148). Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose-6-phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner (By similarity). Regulates neuronal process morphology in the intact central nervous system (CNS) (By similarity). Plays an important role in recruiting SEC16A to endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi vesicle-mediated transport and ERES organization (PubMed:25201882). Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway (By similarity). The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes (By similarity). Phosphorylates PRDX3 (By similarity). By phosphorylating APP on 'Thr-743', which promotes the production and the nuclear translocation of the APP intracellular domain (AICD), regulates dopaminergic neuron apoptosis (PubMed:28720718). Acts as a positive regulator of innate immunity by mediating phosphorylation of RIPK2 downstream of NOD1 and NOD2, thereby enhancing RIPK2 activation (By similarity). Independent of its kinase activity, inhibits the proteasomal degradation of MAPT, thus promoting MAPT oligomerization and secretion (By similarity). In addition, has GTPase activity via its Roc domain which regulates LRKK2 kinase activity (By similarity). Recruited by RAB29/RAB7L1 to overloaded lysosomes where it phosphorylates and stabilizes RAB8A and RAB10 which promote lysosomal content release and suppress lysosomal enlargement through the EHBP1 and EHBP1L1 effector proteins (PubMed:30209220, PubMed:38227290). {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:38227290}.
uniprot
proteins
mass_dalton
284732
uniprot
proteins
mutagenesis
MUTAGEN 1441; /note="R->C: Impaired ability to recruit SEC61A and SEC31A to endoplasmic reticulum exit sites. Impaired ability to regulate ER to Golgi vesicle-mediated transport."; /evidence="ECO:0000269|PubMed:25201882"; MUTAGEN 1441; /note="R->G: Increases kinase activity. Reduces primary ciliogenesis. Causes fragmentation of the trans-Golgi network."; /evidence="ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148"; MUTAGEN 2016; /note="A->T: Does not affect kinase activity and decreases sensitivity towards small molecule kinase inhibitors."; /evidence="ECO:0000269|PubMed:26824392"; MUTAGEN 2019; /note="G->S: Increases kinase activity. Causes loss of dopaminergic neurons in the substantia nigra of 20-month old mice due to increased phosphorylation of APP. Reduces primary ciliogenesis."; /evidence="ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462
uniprot
proteins
post_translational_modification
PTM: Autophosphorylated at Ser-1292 (PubMed:28720718, PubMed:29212815). Autophosphorylation is stimulated by RAB29 (By similarity). Phosphorylation of Ser-910 and Ser-935 or Ser-1444 facilitates interaction with YWHAG (By similarity). Phosphorylation of Ser-910 and/or Ser-935 facilitates interaction with SFN (By similarity). {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29212815}.; PTM: Ubiquitinated by TRIM1; undergoes 'Lys-48'-linked polyubiquitination leading to proteasomal degradation. {ECO:0000250|UniProtKB:Q5S007}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
TKL Ser/Thr protein kinase family
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15541309
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
16487147
uniprot
proteins
pubmed
16504409
uniprot
proteins
pubmed
16532471
uniprot
proteins
pubmed
17120249
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
23395371
uniprot
proteins
pubmed
23526378
uniprot
proteins
pubmed
25201882
uniprot
proteins
pubmed
26824392
uniprot
proteins
pubmed
28720718
uniprot
proteins
pubmed
29125462
uniprot
proteins
pubmed
29212815
uniprot
proteins
pubmed
30209220
uniprot
proteins
pubmed
30398148
uniprot
proteins
pubmed
38227290
uniprot
proteins
sequence_length
2527
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasmic vesicle {ECO:0000250|UniProtKB:Q5S007}. Perikaryon {ECO:0000250|UniProtKB:Q5S007}. Cell projection, axon {ECO:0000250|UniProtKB:Q5S007}. Cell projection, dendrite {ECO:0000250|UniProtKB:Q5S007}. Golgi apparatus membrane {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29212815}; Peripheral membrane protein {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29212815}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:25201882}; Peripheral membrane protein {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:25201882}. Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane {ECO:0000269|PubMed:17120249}. Endosome {ECO:0000269|PubMed:17120249}. Lysosome {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:38227290}. Mitochondrion outer membrane {ECO:0000269|PubMed:17120249}; Peripheral membrane protein {ECO:0000269|PubMed:17120249}. Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:Q5S007}. Cytoplasmic vesicle, phagosome {ECO:0000269|PubMed:38227290}. Note=Colocalized with RAB29 along tubular structures emerging from Golgi apparatus (By similarity). Localizes to endoplasmic reticulum exit sites (ERES), also known as transitional endoplasmic reticulum (tER) (PubMed:25201882). Detected on phagosomes and stressed lysosomes but not detected on autophagosomes induced by starvation (PubMed:38227290). Recruitment to stressed lysosomes is dependent on the ATG8 conjugation system composed of ATG5, ATG12 and ATG16L1 and leads to lysosomal stress-induced activation of LRRK2 (PubMed:38227290). {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:38227290}.
uniprot
proteins