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MBE Advance Access published online on June 1, 2009
Molecular Biology and Evolution, doi:10.1093/molbev/msp109
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© The Author 2009. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

Low exchangeability of selenocysteine, the 21st amino acid, in vertebrate proteins

Sergi Castellano*,{dagger}, Aida M. Andrés*, Elena Bosch, Mònica Bayes{ddagger},§, Roderic Guigó{ddagger} and Andrew G. Clark*

* Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Institut de Biologia Evolutiva (UPF-CSIC), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain
{ddagger} Centre de Regulació Genòmica, Barcelona 08003, Spain
§ Centro Nacional de Genotipado (CeGen), Barcelona 08003, Spain

{dagger} To whom correspondence should be sent at the present address: Janelia Farm Research Campus, Howard Hughes Medical Institute, East Lab, 2E.290. 19700 Helix Drive, Ashburn, VA 20147 (USA). Tel: 571 209 4000 ext. 7160; Fax: 571 209 4095; Email: castellanos{at}janelia.hhmi.org

Received for publication February 1, 2009. Revision received May 4, 2009. 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 non-selenoprotein 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 selenium to protein function is unknown (Gromer et al. 2003, Proc Natl Acad Sci USA 100:12618; 10.1073/pnas.2134510100). 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 selenium, 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

Author contribution: S.C. and A.M.A. contributed equally to this work.


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