7s7g
From Proteopedia
Crystal Structure Analysis of Human VLCAD
Structural highlights
DiseaseACADV_HUMAN Defects in ACADVL are the cause of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD) [MIM:201475. ACADVLD is an autosomal recessive disease which leads to impaired long-chain fatty acid beta-oxidation. It is clinically heterogeneous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting.[1] [2] [3] FunctionACADV_HUMAN Active toward esters of long-chain and very long chain fatty acids such as palmitoyl-CoA, mysritoyl-CoA and stearoyl-CoA. Can accommodate substrate acyl chain lengths as long as 24 carbons, but shows little activity for substrates of less than 12 carbons.[4] Publication Abstract from PubMedVery 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 alpha-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 alpha-helical membrane-binding motif, resulting in pathologic enzyme mislocalization. Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency.,Prew MS, Camara CM, Botzanowski T, Moroco JA, Bloch NB, Levy HR, Seo HS, Dhe-Paganon S, Bird GH, Herce HD, Gygi MA, Escudero S, Wales TE, Engen JR, Walensky LD Nat Commun. 2022 Jun 27;13(1):3669. doi: 10.1038/s41467-022-31466-2. PMID:35760926[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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