ArticleNature communications2022
Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 13 citations in OpenAlex.
- PKM2 knockout facilitates the activation of the AMPK/KLF4/ACADVL pathway, leading to increased oxidative degradation of fatty acids in TNBC.Medical oncology (Northwood, London, England) · 2025Article
- Long-chain acylcarnitine deficiency promotes hepatocarcinogenesis.Acta pharmaceutica Sinica. B · 2025Article
- The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.Nature communications · 2023Article
- Juvenile-Onset Recurrent Rhabdomyolysis Due to Compound Heterozygote Variants in theBrain sciences · 2023Article
- De Novo Design and Synthesis of Polypeptide Immunomodulators for Resetting Macrophage Polarization.Biodesign research · 2023Article
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
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.
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