1. Comprehensive structural characterization of the human AAA+ disaggregase CLPB in the apo- and substrate-bound states reveals a unique mode of action driven by oligomerization.
- Author
-
Wu, Damu, Jakob, Ursula H1, Wu, Damu, Liu, Yan, Dai, Yuhao, Wang, Guopeng, Lu, Guoliang, Chen, Yan, Li, Ningning, Lin, Jinzhong, Gao, Ning, Wu, Damu, Jakob, Ursula H1, Wu, Damu, Liu, Yan, Dai, Yuhao, Wang, Guopeng, Lu, Guoliang, Chen, Yan, Li, Ningning, Lin, Jinzhong, and Gao, Ning
- Abstract
The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space (IMS) and functions to promote the solubilization of various mitochondrial proteins. Loss-of-function CLPB mutations are associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus. How CLPB functions as a disaggregase and the role of its ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. CLPB assembles into homo-tetradecamers in apo-state and is remodeled into homo-dodecamers upon substrate binding. Conserved pore-loops (PLs) on the ATPase domains form a spiral staircase to grip and translocate the substrate in a step-size of 2 amino acid residues. The ANK domain is not only responsible for maintaining the higher-order assembly but also essential for the disaggregase activity. Interactome analysis suggests that the ANK domain may directly interact with a variety of mitochondrial substrates. These results reveal unique properties of CLPB as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.
- Published
- 2023