serval:BIB_DB3E77131FEC
Prediction and experimental characterization of nsSNPs altering human PDZ-binding motifs.
10.1371/journal.pone.0094507
000336909100086
24722214
Gfeller
D.
author
Ernst
A.
author
Jarvik
N.
author
Sidhu
S.S.
author
Bader
G.D.
author
article
2014
PloS One
1932-6203
1932-6203
journal
9
4
e94507
Single nucleotide polymorphisms (SNPs) are a major contributor to genetic and phenotypic variation within populations. Non-synonymous SNPs (nsSNPs) modify the sequence of proteins and can affect their folding or binding properties. Experimental analysis of all nsSNPs is currently unfeasible and therefore computational predictions of the molecular effect of nsSNPs are helpful to guide experimental investigations. While some nsSNPs can be accurately characterized, for instance if they fall into strongly conserved or well annotated regions, the molecular consequences of many others are more challenging to predict. In particular, nsSNPs affecting less structured, and often less conserved regions, are difficult to characterize. Binding sites that mediate protein-protein or other protein interactions are an important class of functional sites on proteins and can be used to help interpret nsSNPs. Binding sites targeted by the PDZ modular peptide recognition domain have recently been characterized. Here we use this data to show that it is possible to computationally identify nsSNPs in PDZ binding motifs that modify or prevent binding to the proteins containing the motifs. We confirm these predictions by experimentally validating a selected subset with ELISA. Our work also highlights the importance of better characterizing linear motifs in proteins as many of these can be affected by genetic variations.
Amino Acid Sequence
Binding Sites
Databases, Genetic
Genome, Human
Humans
Models, Statistical
Molecular Sequence Data
PDZ Domains/genetics
Polymorphism, Single Nucleotide
Protein Binding
Proteins/chemistry
Proteins/genetics
eng
60_published
true
peer-reviewed
University of Lausanne
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