MBE Advance Access originally published online on June 1, 2009
Molecular Biology and Evolution 2009 26(9):2031-2040; doi:10.1093/molbev/msp109
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Research Articles |
Low Exchangeability of Selenocysteine, the 21st Amino Acid, in Vertebrate Proteins
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* Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY
Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Spain
Centre de Regulació Genòmica, Barcelona, Spain
Centro Nacional de Genotipado (CeGen), Barcelona, Spain
E-mail: castellanos{at}janelia.hhmi.org.
Accepted for publication May 22, 2009.
Selenocysteine (Sec), the 21st amino acid, is incorporated into proteins through the recoding of a termination codon, an inefficient translational process mediated by a complex molecular machinery. Sec is a rare amino acid in extant proteins, chemically similar to cysteine (Cys), found in homologous position to Cys of nonselenoprotein families. Selenoproteins account for the dependence of vertebrates on environmental selenium (Se) and have an important role in several Se-deficiency diseases. Selenoproteins are poorly characterized enzymes and reports on the functional exchangeability of Sec with Cys are limited and controversial. Whether the unique role of Sec in some selenoenzymes illustrates the broader contribution of Se to protein function is unknown (Gromer S, Johansson L, Bauer H, Arscott LD, Rauch S, Ballou DP, Williams CH Jr, Schirmer RH, Arnér ES. 2003. Active sites of thioredoxin reductases: why selenoproteins? Proc Natl Acad Sci USA. 100:12618–12623). Here, we address this question from an evolutionary perspective by the simultaneous identification of the patterns of divergence in almost half a billion years of vertebrate evolution and diversity within the human lineage for the full complement of enzymatic Sec residues in these proteomes. We complete this analysis with data for the homologous Cys residues in the same genomes. Our results indicate concerted purifying selection across Sec and Cys sites in all selenoproteomes, consistent with a unique role of Sec in protein function, low exchangeability, and an unknown degree of functional divergence with Cys homologs. The distinct biochemical properties of Sec, rather than the geographical distribution of Se, global O2 levels or Sec metabolic cost, appear to play a major role in driving adaptive changes in vertebrate selenoproteomes. A better understanding of the selenoproteomes and neutral evolutionary patterns in other taxa will be necessary to fully assess the generality of this conclusion.
Key Words: selenium • selenocysteine • cysteine • selenoproteins • vertebrates • exchangeability
1 Author contribution: S.C. and A.M.A. contributed equally to this work.