Protein: Leucine-rich repeat serine/threonine-protein kinase 2 (EC 2.7.11.1) (EC 3.6.5.-) (Dardarin) (Q5S007)
Organism: Homo sapiens (Human)
Function: Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, autophagy, and vesicle trafficking. Is a key regulator of RAB GTPases by regulating the GTP/GDP exchange and interaction partners of RABs through phosphorylation. Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43. Regulates the RAB3IP-catalyzed GDP/GTP exchange for RAB8A through the phosphorylation of 'Thr-72' on RAB8A. Inhibits the interaction between RAB8A and GDI1 and/or GDI2 by phosphorylating 'Thr-72' on RAB8A. Regulates primary ciliogenesis through phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the brain. 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. Regulates neuronal process morphology in the intact central nervous system (CNS). Plays a role in synaptic vesicle trafficking. 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. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Phosphorylates PRDX3. By phosphorylating APP on 'Thr-743', which promotes the production and the nuclear translocation of the APP intracellular domain (AICD), regulates dopaminergic neuron apoptosis. Independent of its kinase activity, inhibits the proteosomal degradation of MAPT, thus promoting MAPT oligomerization and secretion. In addition, has GTPase activity via its Roc domain which regulates LRRK2 kinase activity.
Subcellular location: Cytoplasmic vesicle {ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:16352719, ECO:0000269|PubMed:26014385}. Perikaryon {ECO:0000269|PubMed:17120249}. Golgi apparatus membrane {ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:38127736}; Peripheral membrane protein {ECO:0000269|PubMed:16321986}. Cell projection, axon {ECO:0000269|PubMed:17120249}. Cell projection, dendrite {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:21850687}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:25201882}; Peripheral membrane protein {ECO:0000269|PubMed:16321986}. Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane {ECO:0000269|PubMed:24687852}. Endosome {ECO:0000250|UniProtKB:Q5S006}. Lysosome {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:38227290}. Mitochondrion outer membrane {ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29212815}; Peripheral membrane protein {ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29212815}. Cytoplasm, cytoskeleton {ECO:0000269|PubMed:35266954}. Cytoplasmic vesicle, phagosome {ECO:0000250|UniProtKB:Q5S006}. Note=Colocalized with RAB29 along tubular structures emerging from Golgi apparatus (PubMed:23395371, PubMed:38127736). 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 (By similarity). 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 (By similarity). {ECO:0000250|UniProtKB:Q5S006, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:38127736}.
Interaction partners:
- Ras-related protein Rab-7L1
- Parkinson disease protein 7
- Alpha-synuclein
- E3 ubiquitin-protein ligase parkin
- Cyclin-G-associated kinase
- 14-3-3 protein sigma
- Heat shock protein HSP 90-alpha
- Serine/threonine-protein kinase PINK1, mitochondrial
- Moesin
- Dynamin-1-like protein
Sequence:
MASGSCQGCEEDEETLKKLIVRLNNVQEGKQIETLVQILEDLLVFTYSERASKLFQGKNIHVPLLIVLDSYMRVASVQQVGWSLLCKLIEVCPGTMQSLMGPQDVGNDWEVLGVHQLILKMLTVHNASVNLSVIGLKTLDLLLTSGKITLLILDEESDIFMLIFDAMHSFPANDEVQKLGCKALHVLFERVSEEQLTEFVENKDYMILLSALTNFKDEEEIVLHVLHCLHSLAIPCNNVEVLMSGNVRCYNIVVEAMKAFPMSERIQEVSCCLLHRLTLGNFFNILVLNEVHEFVVKAVQQYPENAALQISALSCLALLTETIFLNQDLEEKNENQENDDEGEEDKLFWLEACYKALTWHRKNKHVQEAACWALNNLLMYQNSLHEKIGDEDGHFPAHREVMLSMLMHSSSKEVFQASANALSTLLEQNVNFRKILLSKGIHLNVLELMQKHIHSPEVAESGCKMLNHLFEGSNTSLDIMAAVVPKILTVMKRHETSLPVQLEALRAILHFIVPGMPEESREDTEFHHKLNMVKKQCFKNDIHKLVLAALNRFIGNPGIQKCGLKVISSIVHFPDALEMLSLEGAMDSVLHTLQMYPDDQEIQCLGLSLIGYLITKKNVFIGTGHLLAKILVSSLYRFKDVAEIQTKGFQTILAILKLSASFSKLLVHHSFDLVIFHQMSSNIMEQKDQQFLNLCCKCFAKVAMDDYLKNVMLERACDQNNSIMVECLLLLGADANQAKEGSSLICQVCEKESSPKLVELLLNSGSREQDVRKALTISIGKGDSQIISLLLRRLALDVANNSICLGGFCIGKVEPSWLGPLFPDKTSNLRKQTNIASTLARMVIRYQMKSAVEEGTASGSDGNFSEDVLSKFDEWTFIPDSSMDSVFAQSDDLDSEGSEGSFLVKKKSNSISVGEFYRDAVLQRCSPNLQRHSNSLGPIFDHEDLLKRKRKILSSDDSLRSSKLQSHMRHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQNALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHISSLSENFLEACPKVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLDMSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKLRKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVRENQLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPKHPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIYLNWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLILADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRAPEVARGNVIYNQQADVYSFGLLLYDILTTGGRIVEGLKFPNEFDELEIQGKLPDPVKEYGCAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIVECMVATHHNSRNASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVEKESWIVSGTQSGTLLVINTEDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTADGKLAIFEDKTVKLKGAAPLKILNIGNVSTPLMCLSESTNSTERNVMWGGCGTKIFSFSNDFTIQKLIETRTSQLFSYAAFSDSNIITVVVDTALYIAKQNSPVVEVWDKKTEKLCGLIDCVHFLREVMVKENKESKHKMSYSGRVKTLCLQKNTALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMTAQLGSLKNVMLVLGYNRKNTEGTQKQKEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEKMRRTSVE