RT Journal Article
SR Electronic
T1 Structure of LRRK1 and mechanisms of autoinhibition and activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.22.517582
DO 10.1101/2022.11.22.517582
A1 Janice M. Reimer
A1 Andrea M. Dickey
A1 Yu Xuan Lin
A1 Robert G. Abrisch
A1 Sebastian Mathea
A1 Deep Chatterjee
A1 Elizabeth J. Fay
A1 Stefan Knapp
A1 Matthew D. Daugherty
A1 Samara L. Reck-Peterson
A1 Andres E. Leschziner
YR 2022
UL http://biorxiv.org/content/early/2022/12/02/2022.11.22.517582.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.