Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2

Kiruphagaran Thangaraju; Róbert Király; Máté A Demény; János András Mótyán; Mónika Fuxreiter; László Fésüs

doi:10.1371/journal.pone.0172189

Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2

PLoS One. 2017 Mar 1;12(3):e0172189. doi: 10.1371/journal.pone.0172189. eCollection 2017.

Authors

Kiruphagaran Thangaraju¹, Róbert Király¹, Máté A Demény¹, János András Mótyán¹, Mónika Fuxreiter^{1

2}, László Fésüs^{1

3}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
² MTA-DE Momentum Laboratory of Protein Dynamics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
³ MTA-DE Stem cell, Apoptosis and Genomics Research Group of Hungarian Academy of Sciences, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

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.

MeSH terms

Alleles*
Amino Acid Substitution
Calcium / chemistry
Calcium / metabolism
Databases, Protein*
Enzyme Stability / genetics
Evolution, Molecular*
Factor XIIIa / chemistry
Factor XIIIa / genetics
Factor XIIIa / metabolism
GTP-Binding Proteins / chemistry*
GTP-Binding Proteins / genetics*
GTP-Binding Proteins / metabolism
Humans
Mutation, Missense*
Protein Glutamine gamma Glutamyltransferase 2
Transglutaminases / chemistry*
Transglutaminases / genetics*
Transglutaminases / metabolism

Substances

TGM2 protein, human
Factor XIIIa
Protein Glutamine gamma Glutamyltransferase 2
TGM3 protein, human
Transglutaminases
GTP-Binding Proteins
Calcium

Grants and funding

This work was supported by the Research University Grant of the University of Debrecen (RH/885/2013) (RK), the Hungarian Scientific Research Fund (OTKA NK 105046) (LF), the New Hungary Development Plan via the TÁMOP-4.2.2.A-11/1/KONV- 2012-0023 “VÉD-ELEM” project co-financed by the European Social Fund (LF), the European Union Framework Programme 7 TRANSPATH ITN 289964 (LF KT) and the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of the TÁMOP 4.2.4. A/2-11-1-2012-0001 ‘National Excellence Programme’ (RK). The support of the Hungarian Scientific Research Fund (OTKA NN 106562) and the Momentum programme (LP2012-41) of the Hungarian Academy of Sciences is gratefully acknowledged (MF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.