PXD029565

PXD029565 is an original dataset announced via ProteomeXchange.

Title	Structural Basis for Defective Membrane Targeting of Mutant Enzyme in Human VLCAD Deficiency
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-06-29
AnnouncementXML	Submission_2022-06-29_07:15:20.019.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John R. Engen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-04 10:16:57	ID requested
⏵ 1	2022-06-29 07:15:21	announced

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, Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency. Nat Commun, 13(1):3669(2022) [pubmed]

submitter keyword: VLCAD

fatty acid oxidation

membrane protein structure

HDX-MS

hydrogen/deuterium exchange mass spectrometry

X-ray crystallography

molecular dynamics

John R Engen
contact affiliation	Department of Chemistry & Chemical Biology, Northeastern University
contact email	j.engen@northeastern.edu
lab head
John R. Engen
contact affiliation	Northeastern University
contact email	j.engen@northeastern.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/06/PXD029565

PRIDE project URI

• PRIDE
  1. PXD029565
     1. Label: PRIDE project
     2. Name: Structural Basis for Defective Membrane Targeting of Mutant Enzyme in Human VLCAD Deficiency