7S7G

Crystal Structure Analysis of Human VLCAD

7S7G の概要

• エントリーDOI: 10.2210/pdb7s7g/pdb
• 分子名称: Very long-chain specific acyl-CoA dehydrogenase, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• 機能のキーワード: dehydrogenase, mitochondrial acyl-coa dehydrogenases, flavin adenine dinucleotide, deficiency, fatty acid oxidation, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 67611.99

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2021-09-15, 公開日: 2022-09-28, 最終更新日: 2024-05-29)

主引用文献

Prew, M.S.,Camara, C.M.,Botzanowski, T.,Moroco, J.A.,Bloch, N.B.,Levy, H.R.,Seo, H.S.,Dhe-Paganon, S.,Bird, G.H.,Herce, H.D.,Gygi, M.A.,Escudero, S.,Wales, T.E.,Engen, J.R.,Walensky, L.D.
Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency.
Nat Commun, 13:3669-3669, 2022

PubMed Abstract: Very long-chain acyl-CoA dehydrogenase (VLCAD) is an inner mitochondrial membrane enzyme that catalyzes the first and rate-limiting step of long-chain fatty acid oxidation. Point mutations in human VLCAD can produce an inborn error of metabolism called VLCAD deficiency that can lead to severe pathophysiologic consequences, including cardiomyopathy, hypoglycemia, and rhabdomyolysis. Discrete mutations in a structurally-uncharacterized C-terminal domain region of VLCAD cause enzymatic deficiency by an incompletely defined mechanism. Here, we conducted a structure-function study, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, computational modeling, and biochemical analyses, to characterize a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted α-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, our data support a structural basis for VLCAD deficiency in patients with discrete mutations in an α-helical membrane-binding motif, resulting in pathologic enzyme mislocalization.

PubMed: 35760926
DOI: 10.1038/s41467-022-31466-2

実験手法

X-RAY DIFFRACTION (1.34 Å)