PXD036417-1

PXD036417 is an original dataset announced via ProteomeXchange.

Title	Counterintuitive structural and functional effects due to naturally-occurring mutations targeting the active site of the disease-associated NQO1 enzyme
Description	Our knowledge on the genetic diversity of the human genome is exponentially growing. However, our capacity to establish genotype-phenotype correlations in a large-scale requires a combination of detailed experimental and computational work. This is a remarkable task in human proteins, which are typically multifunctional and structurally complex. In addition, mutations often prevent the determination of mutant high-resolution structures by X-ray crystallography. We have characterized here the effects of five mutations in the vicinity of the active site of the disease-associated NQO1 protein which are found either in cancer cell lines or in massive exome sequencing analysis in human population. Using a combination of H/D exchange, rapid-flow enzyme kinetics, binding energetics and conformational stability, we show that mutations in both sets may cause counterintuitive functional effects that are explained well by their effects on local stability regarding different functional features. Importantly, mutations predicted to be highly deleterious (even those affecting the same protein residue) may cause mild to catastrophic effects on protein function. These functional effects are not well explained by current predictive bioinformatic tools and evolutionary models that account for site conservation and physicochemical changes upon mutation. Our study also reinforces the notion that naturally-occurring mutations not (yet?) identified as disease-associated can be highly deleterious. Our approach, combining protein biophysics and structural biology tools is readily accessible to broadly increase our understanding of genotype-phenotype correlations and to improve predictive computational tools aimed at distinguishing disease-prone against neutral missense variants in the human genome.
HostingRepository	PRIDE
AnnounceDate	2022-11-23
AnnouncementXML	Submission_2022-11-23_09:36:46.083.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	DmitryLoginov
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	solariX

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-30 14:52:49	ID requested
⏵ 1	2022-11-23 09:36:46	announced
2	2023-11-14 08:58:52	announced	2023-11-14: Updated project metadata.

submitter keyword: Genotype-Phenotype correlations

Protein structure-function

Structural Stability

Catalytic mechanism

PetrMan
contact affiliation	Institute of Microbiology - BioCeV, Academy of Sciences of the Czech Republic
contact email	pman@biomed.cas.cz
lab head
DmitryLoginov
contact affiliation	BioCeV - Institute of Microbiology of the CAS
contact email	dloginov@jcu.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/2022/11/PXD036417

PRIDE project URI

• PRIDE
  1. PXD036417
     1. Label: PRIDE project
     2. Name: Counterintuitive structural and functional effects due to naturally-occurring mutations targeting the active site of the disease-associated NQO1 enzyme