Structure of LRRK1 and mechanisms of autoinhibition and activation

Abstract

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.

Protein kinase C showcases allosteric control: activation of LRRK1

“…This model suggests an alternative mechanism by which, rather than inducing binding, phosphorylation of the CORB loop by PKC likely releases this autoinhibition, allowing for a ‘DYG-in' conformation and a stabilized αC-helix. In support of this second model, F1065A mutation was synergistic with Glu mutation of the three phospho-activation sites to increase basal LRRK1 activity [ 14 ].…”

“…In the time since publication, during the writing of this commentary, a recent study disclosed two cryo-EM structures of autoinhibited LRRK1, with two inhibitory mechanisms. One mechanism required LRRK1 dimerization with the N-terminal ANK domain blocking the kinase domain from substrate binding in trans [ 14 ]. The structures also identified density for the unstructured CORB loop 1048–1085 to thread itself into the active site of the kinase domain as a second layer of autoinhibiton, with F1065 (+1 from S1064 PKC-mediated phosphorylation site) positioned where Y1410 of the DYG motif would normally bind the αC-helix, enforcing a ‘DYG-out' conformation.…”