LRRK2 Q5S007

富亮氨酸重复序列丝氨酸/苏氨酸蛋白激酶2 (EC 2.7.11.1) (EC 3.6.5.-) (Dardarin)

功能描述

丝氨酸/苏氨酸蛋白激酶，磷酸化多种参与神经元可塑性、先天免疫、自噬和囊泡运输等多种过程的蛋白质 (PubMed:17114044, PubMed:20949042, PubMed:21850687, PubMed:22012985, PubMed:23395371, PubMed:24687852, PubMed:25201882, PubMed:26014385, PubMed:26824392, PubMed:27830463, PubMed:28720718, PubMed:29125462, PubMed:29127255, PubMed:29212815, PubMed:30398148, PubMed:30635421)。是RAB GTP酶的关键调节因子，通过磷酸化调节RAB的GTP/GDP交换及相互作用伴侣 (PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29127255, PubMed:29212815, PubMed:30398148, PubMed:30635421)。磷酸化RAB3A、RAB3B、RAB3C、RAB3D、RAB5A、RAB5B、RAB5C、RAB8A、RAB8B、RAB10、RAB12、RAB29、RAB35和RAB43 (PubMed:23395371, PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29127255, PubMed:29212815, PubMed:30398148, PubMed:30635421, PubMed:38127736)。通过磷酸化RAB8A上的'Thr-72'，调节RAB3IP催化的RAB8A GDP/GTP交换 (PubMed:26824392)。通过磷酸化RAB8A上的'Thr-72'，抑制RAB8A与GDI1和/或GDI2之间的相互作用 (PubMed:26824392)。通过磷酸化RAB8A和RAB10调节初级纤毛生成，这促进了脑内的SHH信号传导 (PubMed:29125462, PubMed:30398148)。与RAB29一起，在依赖逆行体的途径中，在溶酶体和高尔基体之间的回收蛋白质（如甘露糖-6-磷酸受体 (M6PR)）的逆向运输途径中发挥作用 (PubMed:23395371)。在完整的中枢神经系统 (CNS) 中调节神经元突形态 (PubMed:17114044)。在突触囊泡运输中发挥作用 (PubMed:24687852)。在招募SEC16A至内质网出口位点 (ERES) 以及调节内质网至高尔基体囊泡介导的运输和ERES组织方面发挥重要作用 (PubMed:25201882)。通过CaMKK/AMPK信号通路的钙依赖性激活正向调节自噬 (PubMed:22012985)。该过程涉及烟酸腺嘌呤二核苷酸磷酸 (NAADP) 受体的激活、溶酶体pH值升高以及溶酶体钙释放 (PubMed:22012985)。磷酸化PRDX3 (PubMed:21850687)。通过磷酸化APP上的'Thr-743'，促进APP胞内结构域 (AICD) 的产生和核转位，从而调节多巴胺能神经元凋亡 (PubMed:28720718)。作为先天免疫的正调节因子，通过介导NOD1和NOD2下游RIPK2的磷酸化，从而增强RIPK2的激活 (PubMed:27830463)。不依赖其激酶活性，抑制MAPT的蛋白酶体降解，从而促进MAPT寡聚化和分泌 (PubMed:26014385)。此外，通过其Roc结构域具有GTP酶活性，该活性调节LRRK2激酶活性 (PubMed:18230735, PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29212815)。被RAB29/RAB7L1招募到过载的溶酶体，在那里磷酸化并稳定RAB8A和RAB10，通过EHBP1和EHBP1L1效应蛋白促进溶酶体内容物释放并抑制溶酶体增大 (PubMed:30209220, PubMed:38227290)。 {ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:20949042, ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22012985, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:24687852, ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:26014385, ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:27830463, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736, ECO:0000269|PubMed:38227290}.

组织特异性

Expressed in pyramidal neurons in all cortical laminae of the visual cortex, in neurons of the substantia nigra pars compacta and caudate putamen (at protein level). Expressed in neutrophils (at protein level) (PubMed:29127255). Expressed in the brain. Expressed throughout the adult brain, but at a lower level than in heart and liver. Also expressed in placenta, lung, skeletal muscle, kidney and pancreas. In the brain, expressed in the cerebellum, cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, temporal lobe and putamen. Expression is particularly high in brain dopaminoceptive areas.

亚细胞定位

Cytoplasmic vesicle