PXD046749

PXD046749 is an original dataset announced via ProteomeXchange.

Title	Insights into PH1 disease mechanisms from the analyses of the structural stability and dynamics of AGT variants
Description	Primary hyperoxaluria type I (PH1) is a genetic disease caused by a deficiency in the peroxisomal alanine:glyoxylate aminotransferase (AGT) activity. Mutations in AGT mostly cause protein mistargeting and enhanced aggregation, although the molecular and structural basis of these mechanisms are unknown. In this work, we use hydrogen-deuterium exchange monitored by mass spectrometry (HDX-MS) to provide novel insight into these pathogenic mechanisms. We characterize the wild-type (WT) protein, the LM variant (containing the mutations P11L and I340M, a haplotype more frequent in PH1 patients) and the LM G170R (the most common genotype in PH1, introducing the G170R mutation on the LM background). Our study provides the first experimental analysis of the local stability and dynamics of AGT, showing that stability is heterogeneous in the native state and providing a blueprint for frustrated regions with potentially functional relevance. The LM and LM G170R variants destabilize locally the structure. Enzymatic transamination of the PLP bound to AGT hardly affects stability. Our study thus supports that AGT misfolding is not caused by dramatic effects on the stability and dynamics of the holo-protein.
HostingRepository	PRIDE
AnnounceDate	2024-01-25
AnnouncementXML	Submission_2024-01-25_02:13:40.068.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pavla Vankova
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-07 08:17:36	ID requested
⏵ 1	2024-01-25 02:13:40	announced

10.1002/1873-3468.14800;

ProteomeXchange project tag: Hydrogen Deuterium Exchange (HDX-MS), EPIC-XS

submitter keyword: protein stability

protein dynamics

functional sites

disease-causing variants

primary hyperoxaluria

Petr Man
contact affiliation	Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology of the Czech Acad Sci, Prumyslova 595, 252 50 Vestec, Czech Republic
contact email	pman@biomed.cas.cz
lab head
Pavla Vankova
contact affiliation	Institute of Biotechnology of the Czech Academy of Sciences, BioCeV, Prumyslova 595, 252 50 Vestec, Czech Republic
contact email	pavla.vankova@ibt.cas.cz
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/2024/01/PXD046749

PRIDE project URI

• PRIDE
  1. PXD046749
     1. Label: PRIDE project
     2. Name: Insights into PH1 disease mechanisms from the analyses of the structural stability and dynamics of AGT variants