Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency

Michelle S. Prew, Christina M. Camara, Thomas Botzanowski, Jamie A. Moroco, Noah B. Bloch, Hannah R. Levy, Hyuk-Soo Seo, Sirano Dhe-Paganon, Gregory H. Bird, Henry D. Herce, Micah A. Gygi, Silvia Escudero, Thomas E. Wales, John R. Engen and Loren D. Walensky ()
Additional contact information
Michelle S. Prew: Dana-Farber Cancer Institute
Christina M. Camara: Dana-Farber Cancer Institute
Thomas Botzanowski: Northeastern University
Jamie A. Moroco: Northeastern University
Noah B. Bloch: Dana-Farber Cancer Institute
Hannah R. Levy: Dana-Farber Cancer Institute
Hyuk-Soo Seo: Dana-Farber Cancer Institute
Sirano Dhe-Paganon: Dana-Farber Cancer Institute
Gregory H. Bird: Dana-Farber Cancer Institute
Henry D. Herce: Dana-Farber Cancer Institute
Micah A. Gygi: Dana-Farber Cancer Institute
Silvia Escudero: Dana-Farber Cancer Institute
Thomas E. Wales: Northeastern University
John R. Engen: Northeastern University
Loren D. Walensky: Dana-Farber Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31466-2

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