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Structure of LRRK1 and mechanisms of autoinhibition and activation
bioRxiv - Biochemistry Pub Date : 2022-12-02 , DOI: 10.1101/2022.11.22.517582
Janice M Reimer, Andrea M Dickey, Yu Xuan Lin, Robert G Abrisch, Sebastian Mathea, Deep Chatterjee, Elizabeth J Fay, Matthew D Daugherty, Samara L Reck-Peterson, Andres E Leschziner

Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, their disease associations are strikingly different: LRRK2 is involved in familial Parkinson's Disease (PD) while LRRK1 is linked to bone diseases. Furthermore, PD-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function. To understand these differences, we solved cryo-EM structures of LRRK1 in its monomeric and dimeric forms. Both differ from the corresponding LRRK2 structures. Unlike LRRK2, which is sterically autoinhibited as a monomer, LRRK1 is sterically autoinhibited in a dimer-dependent manner. LRRK1 has an additional level of autoinhibition that prevents activation of the kinase and is absent in LRRK2. Finally, we place the structural signatures of LRRK1 and LRRK2 in the context of the evolution of the LRRK family of proteins.

中文翻译:

LRRK1的结构及自身抑制和激活机制

富含亮氨酸重复激酶 1 和 2(LRRK1 和 LRRK2)是人类 ROCO 蛋白家族的同系物。尽管它们共享域结构并参与细胞内运输,但它们的疾病关联却截然不同:LRRK2 与家族性帕金森病 (PD) 相关,而 LRRK1 与骨骼疾病有关。此外,LRRK2 中的 PD 相关突变通常是常染色体显性功能获得,而 LRRK1 中的突变是常染色体隐性功能丧失。为了理解这些差异,我们解析了 LRRK1 的单体和二聚体形式的冷冻电镜结构。两者都不同于相应的 LRRK2 结构。与 LRRK2 作为单体进行空间自抑制不同,LRRK1 以二聚体依赖性方式进行空间自抑制。LRRK1 具有额外的自抑制水平,可防止激酶激活,而 LRRK2 中不存在。最后,我们将 LRRK1 和 LRRK2 的结构特征置于 LRRK 蛋白质家族进化的背景下。
更新日期:2022-12-03
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