7XBK

Structure and mechanism of a mitochondrial AAA+ disaggregase CLPB

Summary for 7XBK

• Entry DOI: 10.2210/pdb7xbk/pdb
• EMDB information: 33104
• Descriptor: Isoform 2 of Caseinolytic peptidase B protein homolog, Unknown peptide, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: clpb, aaa-atpase, chaperone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 685813.71

Authors

Wu, D.,Liu, Y.,Dai, Y.,Wang, G.,Lu, G.,Chen, Y.,Li, N.,Lin, J.,Gao, N. (deposition date: 2022-03-21, release date: 2023-01-25, Last modification date: 2024-06-26)

Primary citation

Wu, D.,Liu, Y.,Dai, Y.,Wang, G.,Lu, G.,Chen, Y.,Li, N.,Lin, J.,Gao, N.
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.
Plos Biol., 21:e3001987-e3001987, 2023

PubMed 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.

PubMed: 36745679
DOI: 10.1371/journal.pbio.3001987

Experimental method

ELECTRON MICROSCOPY (3.7 Å)