Structural Basis of Impaired Disaggregase Function in the Oxidation-sensitive Skd3 Mutant Causing 3-methylglutaconic Aciduria

Authors

Sukyeong Lee
Sang Bum Lee
Nuri Sung
Wendy W Xu
Changsoo Chang
Hyun-Eui Kim
Andre Catic
Francis T F Tsai

Publication Date

4-11-2023

Journal

Nature Communications

Abstract

Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines to survey and maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled protein disaggregase essential for preserving mitochondrial integrity and structure. SKD3 deficiency causes 3-methylglutaconic aciduria type VII (MGCA7) and early death in infants, while mutations in the ATPase domain impair protein disaggregation with the observed loss-of-function correlating with disease severity. How mutations in the non-catalytic N-domain cause disease is unknown. Here, we show that the disease-associated N-domain mutation, Y272C, forms an intramolecular disulfide bond with Cys267 and severely impairs SKD3

Keywords

Humans, Infant, Metabolism, Inborn Errors, Mitochondria, Mutation, Protein Domains, Heat-Shock Proteins, X-ray crystallography, Chaperones