title: Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2.
abstract: Transglutaminases (TGMs) catalyze Ca2+-dependent transamidation of proteins with specified roles in blood clotting (F13a) and in cornification (TGM1, TGM3). The ubiquitous TGM2 has well described enzymatic and non-enzymatic functions but in-spite of numerous studies its physiological function in humans has not been defined. We compared data on non-synonymous single nucleotide variations (nsSNVs) and loss-of-function variants on TGM1-7 and F13a from the Exome aggregation consortium dataset, and used computational and biochemical analysis to reveal the roles of damaging nsSNVs of TGM2. TGM2 and F13a display rarer damaging nsSNV sites than other TGMs and sequence of TGM2, F13a and TGM1 are evolutionary constrained. TGM2 nsSNVs are predicted to destabilize protein structure, influence Ca2+ and GTP regulation, and non-enzymatic interactions, but none coincide with conserved functional sites. We have experimentally characterized six TGM2 allelic variants detected so far in homozygous form, out of which only one, p.Arg222Gln, has decreased activities. Published exome sequencing data from various populations have not uncovered individuals with homozygous loss-of-function variants for TGM2, TGM3 and TGM7. Thus it can be concluded that human transglutaminases differ in harboring damaging variants and TGM2 is under purifying selection suggesting that it may have so far not revealed physiological functions.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Kiruphagaran
authors.initials: K
authors.lastname: Thangaraju
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Király
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Máté A
authors.initials: MA
authors.lastname: Demény
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: András Mótyán
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.|MTA-DE Momentum Laboratory of Protein Dynamics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Fuxreiter
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.|MTA-DE Stem cell, Apoptosis and Genomics Research Group of Hungarian Academy of Sciences, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Fésüs
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D004795:Enzyme Stability / Q000235:genetics; D019143:Evolution, Molecular; D026122:Factor XIIIa / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: C000717608:TGM2 protein, human; D026122:Factor XIIIa; D000091345:Protein Glutamine gamma Glutamyltransferase 2; C498712:TGM3 protein, human; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002118:Calcium