lmmol · Proteins

Leucine-rich repeat serine/threonine-protein kinase 2

UniProt Q5S007 Organism Homo sapiens Gene LRRK2, PARK8 EC 2.7.11.1, 3.6.5.-

Also known as: LRRK2, PARK8

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. 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, RAB29, 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. Acts as a positive regulator of innate immunity by mediating phosphorylation of RIPK2 downstream of NOD1 and NOD2, thereby enhancing RIPK2 activation. Independent of its kinase activity, inhibits the proteasomal degradation of MAPT, thus promoting MAPT oligomerization and secretion. In addition, has GTPase activity via its Roc domain which regulates LRRK2 kinase activity. 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.

Classification

Family (Pfam)
PF23745 ANK_LRRK2, PF23744 ARM_LRRK2, PF23748 Beta-prop_LRRK2, PF16095 COR-A, PF25497 COR-B, PF13855 LRR_8, PF00069 Pkinase, PF08477 Roc
InterPro
ANK_LRRK2, Ankyrin_rpt-contain_sf, ARM-like, ARM-type_fold, ARM_LRRK2, Beta-prop_LRRK2, COR-A, COR-B, Kinase-like_dom_sf, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf, P-loop_NTPase, Prot_kinase_dom, Protein_kinase_ATP_BS, ROC, Ser/Thr_kinase_AS, Ser_Thr_Kinases_DiverseReg, Small_GTP-bd, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
Functional cluster
Zinc-Finger & Chromatin Regulatory Proteins

Experimental structures · PDB · 44

A predicted model is available from AlphaFold.

Gene Ontology · 157

Disease associations

Neighborhood · nearest proteins

LRRK2Lrrk2AtrATRRAB10FXY2RAB29
Nearest neighbours of Leucine-rich repeat serine/threonine-protein kinase 2: 3 by sequence/function similarity (left); 3 co-cited in the literature (right).

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Literature · 69 cited papers

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