Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria

Sukyeong Lee, Sang Bum Lee, Nuri Sung, Wendy W. Xu, Changsoo Chang, Hyun-Eui Kim, Andre Catic and Francis T. F. Tsai ()
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Sukyeong Lee: Baylor College of Medicine
Sang Bum Lee: Baylor College of Medicine
Nuri Sung: Baylor College of Medicine
Wendy W. Xu: Baylor College of Medicine
Changsoo Chang: Structural Biology Center, X-ray Science Division, Argonne National Laboratory
Hyun-Eui Kim: University of Texas Health Science Center at Houston
Andre Catic: Baylor College of Medicine
Francis T. F. Tsai: Baylor College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: 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 SKD3Y272C function under oxidizing conditions and in living cells. While Cys267 and Tyr272 are found in all SKD3 isoforms, isoform-1 features an additional α-helix that may compete with substrate-binding as suggested by crystal structure analyses and in silico modeling, underscoring the importance of the N-domain to SKD3 function.

Date: 2023
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DOI: 10.1038/s41467-023-37657-9

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