title: A survey of proteins encoded by non-synonymous single nucleotide polymorphisms reveals a significant fraction with altered stability and activity.
abstract: On average, each human gene has approximately four SNPs (single nucleotide polymorphisms) in the coding region, half of which are nsSNPs (non-synonymous SNPs) or missense SNPs. Current attention is focused on those that are known to perturb function and are strongly linked to disease. However, the vast majority of SNPs have not been investigated for the possibility of causing disease. We set out to assess the fraction of nsSNPs that encode proteins that have altered stability and activity, for this class of variants would be candidates to perturb cellular function. We tested the thermostability and, where possible, the catalytic activity for the most common variant (wild-type) and minor variants (total of 46 SNPs) for 16 human enzymes for which the three-dimensional structures were known. There were significant differences in the stability of almost half of the variants (48%) compared with their wild-type counterparts. The catalytic efficiency of approx. 14 variants was significantly altered, including several variants of human PKM2 (pyruvate kinase muscle 2). Two PKM2 variants, S437Y and E28K, also exhibited changes in their allosteric regulation compared with the wild-type enzyme. The high proportion of nsSNPs that affect protein stability and function, albeit subtly, underscores the need for experimental analysis of the diverse human proteome.
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Room 839, MaRS Centre, South Tower, Toronto, ON, Canada M5G 1L7.
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasney
authors.forename: Irene
authors.initials: I
authors.lastname: Chau
authors.forename: Bum Soo
authors.initials: BS
authors.lastname: Hong
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.forename: Peter
authors.initials: P
authors.lastname: Loppnau
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shi
authors.forename: John
authors.initials: J
authors.lastname: Moult
authors.forename: Aled M
authors.initials: AM
authors.lastname: Edwards
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Hee Won
authors.initials: HW
authors.lastname: Park
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
mesh_terms: D000494:Allosteric Regulation; D015239:Arylsulfotransferase; D005454:Fluorescence Polarization; D006801:Humans; D007700:Kinetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000502:physiology; D017510:Protein Folding; D055550:Protein Stability; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011770:Pyruvate Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins; D011484:Protein-Arginine N-Methyltransferases; D011770:Pyruvate Kinase; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C403170:monoamine-sulfating phenol sulfotransferase; C508544:SIRT5 protein, human; D037761:Sirtuins