8e05
From Proteopedia
Structure of dimeric LRRK1
Structural highlights
DiseaseLRRK1_HUMAN Osteosclerotic metaphyseal dysplasia. The disease is caused by variants affecting the gene represented in this entry. FunctionLRRK1_HUMAN Serine/threonine-protein kinase which phosphorylates RAB proteins involved in intracellular trafficking (PubMed:36040231). Phosphorylates RAB7A; this activity is dependent on protein kinase C (PKC) activation (PubMed:36040231, PubMed:37558661, PubMed:37857821). Plays a role in the negative regulation of bone mass, acting through the maturation of osteoclasts (By similarity).[UniProtKB:Q3UHC2][1] [2] [3] Publication Abstract from PubMedLeucine 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 while LRRK1 is linked to bone diseases. Furthermore, Parkinson's disease-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function. Here, 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. Structure of LRRK1 and mechanisms of autoinhibition and activation.,Reimer JM, Dickey AM, Lin YX, Abrisch RG, Mathea S, Chatterjee D, Fay EJ, Knapp S, Daugherty MD, Reck-Peterson SL, Leschziner AE Nat Struct Mol Biol. 2023 Nov;30(11):1735-1745. doi: 10.1038/s41594-023-01109-1. , Epub 2023 Oct 19. PMID:37857821[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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