On the Allosteric Effect of nsSNPs and the Emerging Importance of Allosteric Polymorphism

Page view(s)
20
Checked on Jun 08, 2024
On the Allosteric Effect of nsSNPs and the Emerging Importance of Allosteric Polymorphism
Title:
On the Allosteric Effect of nsSNPs and the Emerging Importance of Allosteric Polymorphism
Journal Title:
Journal of Molecular Biology
Publication Date:
12 July 2019
Citation:
Wei-Ven Tee, Enrico Guarnera, Igor N. Berezovsky, On the Allosteric Effect of nsSNPs and the Emerging Importance of Allosteric Polymorphism, Journal of Molecular Biology, Volume 431, Issue 19, 2019, Pages 3933-3942, ISSN 0022-2836, https://doi.org/10.1016/j.jmb.2019.07.012.
Abstract:
The molecular mechanisms of pathological non-synonymous single-nucleotide polymorphisms are still the object of intensive research. To this end, we explore here whether non-synonymous single-nucleotide polymorphisms can work via allosteric mechanisms. Using structure-based statistical mechanical model of allostery and analyzing energetics of the effects of mutations in a set of 27 proteins with at least 50 pathological SNPs in each molecule, we found that, indeed, some SNPs can work allosterically. We illustrate the molecular basis of disease phenotypes caused by allosteric SNPs with the case studies of human galactose 1-phosphate uridyltransferase (GALT) and glucose-6-phosphate dehydrogenase (G6PD). We also found that mutations of a number of other residues in the protein may cause modulation comparable to those observed for known pathological SNPs. In order to explain this, we propose a notion of allosteric polymorphism, which implies the presence of a number of critical positions in the protein sequence, whose mutations can allosterically disrupt the protein function and result in a disease phenotype. We conclude that the emerging importance of allosteric polymorphism calls for the development of computational framework for analyzing the allosteric effects of mutations and their role in the modulation of protein activity.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
This research is supported by core funding from the Bioinformatics Institute, ARES.
Description:
ISSN:
0022-2836
1089-8638
Files uploaded:

File Size Format Action
1095a-on-the-allosteric-effect-of.pdf 5.92 MB PDF Open