8DEH

Ankyrin domain of SKD3

Summary for 8DEH

• Entry DOI: 10.2210/pdb8deh/pdb
• Descriptor: Caseinolytic peptidase B protein homolog (2 entities in total)
• Functional Keywords: mitochondria, chaperone, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 24946.90

Authors

Lee, S.,Tsai, F.T.F. (deposition date: 2022-06-20, release date: 2023-04-19, Last modification date: 2024-05-01)

Primary citation

Lee, S.,Lee, S.B.,Sung, N.,Xu, W.W.,Chang, C.,Kim, H.E.,Catic, A.,Tsai, F.T.F.
Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria.
Nat Commun, 14:2028-2028, 2023

PubMed 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 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.

PubMed: 37041140
DOI: 10.1038/s41467-023-37657-9

Experimental method

X-RAY DIFFRACTION (1.815 Å)