| IED ID | IndEnz0017000029 |
| Enzyme Type ID | manganese peroxidase000029 |
| Protein Name |
Leucine-rich repeat serine/threonine-protein kinase 2 EC 2.7.11.1 EC 3.6.5.- |
| Gene Name | Lrrk2 |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MASGACQGCEEEEEEEALKKLIVRLNNVQEGKQIETLLQLLEDMLVFTYSDRASKLFEDKNFHVPLLIVLDSYMRVASVQQAGWSLLCKLIEVCPGTLQSLIGPQDIGNDWEVLGIHRLILKMLTVHHANVNLSIVGLKALDLLLDSGKLTLLILDEECDIFLLIFDAMHRYSANDEVQKLGCKALHVLFERVSEEQLTEFVENKDYTILLSTFGSFRRDKEIVYHVLCCLHSLAVTCSNVEVLMSGNVRCYNLVVEAMKAFPTNENIQEVSCSLFQKLTLGNFFNILVLNEVHVFVVKAVRQYPENAALQISALSCLALLTETIFLNQDLEERSETQEQSEEEDSEKLFWLEPCYKALVRHRKDKHVQEAACWALNNLLMYQNSLHEKIGDEDGQFPAHREVMLSMLMHSSSKDVFQAAAHALSTLLEQNVNFRKILLAKGVYLNVLELMQKHAHAPEVAESGCKMLSHLFEGSNPSLDTMAAVVPKILTVMKAHGTSLSVQLEALRAILHFVVPGLLEESREDSQCRPNVLRKQCFRTDIHKLVLVALNRFIGNPGIQKCGLKVISSLAHLPDATETLSLQGAVDSVLHTLQMYPDDQEIQCLGLHLMGCLMTKKNFCIGTGHLLAKILASTLQRFKDVAEVQTTGLQTTLSILELSVSFSKLLVHYSFDVVIFHQMSSSVVEQKDEQFLNLCCKCFAKVAVDDELKNTMLERACDQNNSIMVECLLLLGADANQVKGATSLIYQVCEKESSPKLVELLLNGGCREQDVRKALTVSIQKGDSQVISLLLRKLALDLANNSICLGGFGIGKIDPSWLGPLFPDKSSNLRKQTNTGSVLARKVLRYQMRNTLQEGVASGSDGKFSEDALAKFGEWTFIPDSSMDSVFGQSDDLDSEGSESSFLVKRKSNSISVGEVYRDLALQRCSPNAQRHSNSLGPVFDHEDLLRRKRKILSSDESLRSSRLPSHMRQSDSSSSLASEREHITSLDLSANELKDIDALSQKCCLSSHLEHLTKLELHQNSLTSFPQQLCETLKCLIHLDLHSNKFTSFPSFVLKMPRITNLDASRNDIGPTVVLDPAMKCPSLKQLNLSYNQLSSIPENLAQVVEKLEQLLLEGNKISGICSPLSLKELKILNLSKNHIPSLPGDFLEACSKVESFSARMNFLAAMPALPSSITSLKLSQNSFTCIPEAIFSLPHLRSLDMSHNNIECLPGPAHWKSLNLRELIFSKNQISTLDFSENPHVWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDGLHLNFDFKHVGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKMKKPELGMQGATVGIDVRDWSIQIRGKRRKDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACISKITKELLNKRGFPTIRDYHFVNATEESDALAKLRKTIINESLNFKIRDQPVVGQLIPDCYVELEKIILSERKAVPTEFPVINRKHLLQLVNEHQLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKVMAQILTVKVDGCLKHPKGIISRRDVEKFLSKKKRFPKNYMMQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPFMLSGRERALRPNRMYWRQGIYLNWSPEAYCLVGSEVLDNRPESFLKITVPSCRKGCILLGRVVDHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDELMKKAEEGDLLINPDQPRLTIPISQIAPDLILADLPRNIMLNNDELEFEEAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRAPEVARGNVIYNQQADVYSFGLLLHDIWTTGSRIMEGLRFPNEFDELAIQGKLPDPVKEYGCAPWPMVEKLITKCLKENPQERPTSAQVFDILNSAELICLMRHILIPKNIIVECMVATNLNSKSATLWLGCGNTEKGQLSLFDLNTERYSYEEVADSRILCLALVHLAAEKESWVVCGTQSGALLVINVEEETKRHTLEKMTDSVTCLHCNSLAKQSKQSNFLLVGTADGNLMIFEDKAVKCKGAAPLKTLHIGDVSTPLMCLSESLNSSERHITWGGCGTKVFSFSNDFTIQKLIETKTNQLFSYAAFSDSNIIALAVDTALYIAKKNSPVVEVWDKKTEKLCELIDCVHFLKEVMVKLNKESKHQLSYSGRVKALCLQKNTALWIGTGGGHILLLDLSTRRVIRTIHNFCDSVRAMATAQLGSLKNVMLVLGYKRKSTEGIQEQKEIQSCLSIWDLNLPHEVQNLEKHIEVRTELADKMRKTSVE |
| Enzyme Length | 2527 |
| Uniprot Accession Number | Q5S006 |
| Absorption | |
| Active Site | ACT_SITE 1994; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-ProRule:PRU10027" |
| Activity Regulation | ACTIVITY REGULATION: Kinase activity is regulated by the GTPase activity of the ROC domain (Probable). GTP-bound LLRK2 kinase activity is stimulated by RAB29 (Probable). Inhibited by small molecule inhibitors MLi-2 and LRRK2-IN-1 (PubMed:26824392, PubMed:28720718). {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000305|PubMed:29212815}. |
| Binding Site | BINDING 1906; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462}; CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462}; CATALYTIC ACTIVITY: Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; Evidence={ECO:0000250|UniProtKB:Q5S007}; |
| DNA Binding | |
| EC Number | 2.7.11.1; 3.6.5.- |
| Enzyme Function | FUNCTION: Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, autophagy, and vesicle trafficking (PubMed:26824392, PubMed:29125462, PubMed:28720718, PubMed:30398148, PubMed:29212815). 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:30398148, PubMed:29212815, PubMed:29125462). Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43 (PubMed:26824392, PubMed:28720718, PubMed:30398148, PubMed:29212815). 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). Independent of its kinase activity, inhibits the proteosomal 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). {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:30398148}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 1341..1348; /note=GTP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00758; NP_BIND 1885..1893; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159; NP_BIND 2098..2121; /note=GTP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00758; NP_BIND 2295..2298; /note=GTP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00758 |
| Features | Active site (1); Binding site (1); Chain (1); Coiled coil (1); Compositional bias (1); Domain (2); Modified residue (6); Mutagenesis (4); Nucleotide binding (4); Region (1); Repeat (19); Sequence conflict (5) |
| Keywords | ATP-binding;Autophagy;Cell junction;Cell projection;Coiled coil;Cytoplasmic vesicle;Differentiation;Endoplasmic reticulum;Endosome;GTP-binding;GTPase activation;Golgi apparatus;Hydrolase;Kinase;Leucine-rich repeat;Lysosome;Membrane;Mitochondrion;Mitochondrion outer membrane;Nucleotide-binding;Phosphoprotein;Reference proteome;Repeat;Serine/threonine-protein kinase;Synapse;Transferase;WD repeat |
| Interact With | Q9EPJ9; O55143; Q8K1M6; Itself; P46460; P31324; Q9CQV8; P62259; P61982; P68510; P68254; P63101; P26038 |
| Induction | |
| 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}. Mitochondrion outer membrane {ECO:0000269|PubMed:17120249}; Peripheral membrane protein {ECO:0000269|PubMed:17120249}. 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). {ECO:0000250|UniProtKB:Q5S007, ECO:0000269|PubMed:25201882}. |
| Modified Residue | MOD_RES 910; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q5S007"; MOD_RES 935; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:26824392, ECO:0007744|PubMed:21183079"; MOD_RES 955; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q5S007"; MOD_RES 973; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q5S007"; MOD_RES 1292; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q5S007"; MOD_RES 1444; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q5S007" |
| Post Translational Modification | PTM: Autophosphorylated (PubMed:28720718, PubMed:29212815). 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}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 11004510; 11217851; 12466851; 16771836; 16980962; 17101029; 17114044; 17341485; 17623048; 18045479; 18367605; 18445495; 18790059; 19142648; 19176810; 19196961; 19536328; 19545277; 19667187; 19740074; 19890007; 20016100; 20064389; 20079710; 20130188; 20146535; 20403420; 20457918; 20595391; 20642453; 20659021; 20728949; 20729864; 20850369; 20876399; 21048939; 21168496; 21307259; 21370995; 21390248; 21677750; 21695257; 21806997; 21828077; 21972245; 21983832; 22080837; 22166428; 22230652; 22253261; 22302802; 22335897; 22357653; 22363216; 22423108; 22496842; 22539006; 22612223; 22615783; 22639965; 22647713; 22713584; 22723946; 22736029; 22850484; 22863203; 22899650; 22952686; 22988862; 23066449; 23082216; 23125283; 23183827; 23190742; 23231918; 23241745; 23270607; 23318930; 23526378; 23600457; 23646112; 23675505; 23886663; 23936174; 23937259; 23949442; 24046356; 24113872; 24167564; 24275654; 24282027; 24427314; 24464040; 24510904; 24633735; 24652679; 24682598; 24687852; 24733019; 24794857; 24952961; 25107341; 25301747; 25309331; 25343991; 25356398; 25360523; 25500533; 25501810; 25609428; 25830304; 25834052; 25836420; 25854701; 25926623; 25939886; 26005538; 26067490; 26123485; 26237551; 26251043; 26268594; 26282470; 26355680; 26363496; 26365310; 26375402; 26384650; 26546614; 26646749; 26758690; 26811536; 26943952; 26979073; 27273569; 27357661; 27364102; 27378696; 27383589; 27411784; 27413152; 27424887; 27474410; 27539321; 27658356; 27798112; 27830463; 27872856; 27890708; 27903237; 28098219; 28103901; 28120865; 28168579; 28202664; 28292328; 28330897; 28508149; 28576705; 28582422; 28710481; 28821568; 28893563; 28930069; 29038245; 29054882; 29056298; 29088368; 29246723; 29305532; 29386392; 29408508; 29434188; 29472933; 29541021; 29707617; 29743203; 29760073; 29789389; 29800472; 29855356; 29875204; 29891719; 29908325; 29917075; 30048714; 30089035; 30150626; 30172844; 30194047; 30209220; 30249796; 30291536; 30420654; 30571694; 30670047; 30720180; 30890692; 30927072; 30949397; 30983487; 31046837; 31102768; 31149340; 31166814; 31554740; 31555076; 31813996; 31821596; 32057291; 32075681; 32111741; 32164260; 32247534; 32434048; 32477237; 32631998; 32643832; 32853409; 33006315; 33007689; 33055242; 33105882; 33132310; 33135724; 33213462; 33298972; 33300446; 33367571; 33459343; 33483550; 33498474; 33629273; 33706934; 34043193; 34077533; 34145320; 34313548; 34340748; 34409578; 34419621; 34446559; 34658337; 34686322; 34749824; 34759048; 34831434; 35012605; |
| Motif | |
| Gene Encoded By | |
| Mass | 284,732 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:46608; RHEA:17989; RHEA:19669 |
| Cross Reference Brenda |