Proteomics

Dataset Information

0

Structural Basis for Defective Membrane Targeting of Mutant Enzyme in Human VLCAD Deficiency


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 analysis, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, and computational modeling, to identify a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted a-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, we find that enzyme mislocalization underlies the metabolic deficiency syndrome of patients bearing specific mutations that disrupt the structure of an a-helical membrane binding region of VLCAD.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: John R. Engen  

LAB HEAD: John R Engen

PROVIDER: PXD029565 | Pride | 2022-06-29

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
10_1_VLCAD_lipo_KCl_10m.raw.zip Raw
10_1_VLCAD_lipo_KCl_10s.raw.zip Raw
10_1_VLCAD_lipo_KCl_1h.raw.zip Raw
10_1_VLCAD_lipo_KCl_1m.raw.zip Raw
10_1_VLCAD_lipo_KCl_UND1.raw.zip Raw
Items per page:
1 - 5 of 102
altmetric image

Publications


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 b  ...[more]

Similar Datasets

2022-06-14 | PXD030492 | Pride
2023-04-14 | PXD025717 | Pride
2020-06-17 | PXD016059 | Pride
2023-04-07 | PXD040227 | Pride
2021-08-26 | PXD024479 | Pride
2021-08-16 | PXD022944 | Pride
2024-01-19 | PXD040917 | Pride
2023-03-11 | PXD035741 | Pride
2022-02-22 | PXD029402 | Pride
2023-03-09 | PXD035723 | Pride