biostudies-literatureReimer JMNIGMS NIH HHS1735-1745https://www.ebi.ac.uk/biostudies/studies/S-EPMC10643122biostudies-literatureUnknown30(11)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 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.Nature structural & molecular biologyStructure of LRRK1 and mechanisms of autoinhibition and activation.PMC10643122R35 GM133633Knapp SDickey AMLin YXMathea SLeschziner AEFay EJReck-Peterson SLAbrisch RGReimer JMChatterjee DDaugherty MDfalseStructure of LRRK1 and mechanisms of autoinhibition and activation.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 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.2023-01-01T00:00:00Z2023 Nov2026-07-14T19:18:00.817Z2025-04-04T07:24:26.449ZS-EPMC106431223785782110.1038/s41594-023-01109-1