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MBE Advance Access published online on January 22, 2004
Molecular Biology and Evolution, doi:10.1093/molbev/msh055
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2004; all rights reserved
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Accepted November 4, 2003
© 2004 Society for Molecular Biology and Evolution

Original Articles

Evolution of the Multi-Functional Protein Tyrosine Phosphatase Family

Birgit Pils 1 and Jörg Schultz 1*

1 Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Ihnestr. 73, 14195 Berlin, Germany

* To whom correspondence should be addressed. E-mail: Joerg.Schultz{at}biozentrum.uni-wuerzburg.de.


  Abstract

The protein tyrosine phosphatase (PTP) family plays a central role in signal transduction pathways by controlling the phosphorylation state of serine, threonine and tyrosine residues. PTPs can be divided into dual specificity phosphatases and the classical PTPs, which can comprise of one or two phosphatase domains. We studied amino acid substitutions at functional sites in the phosphatase domain and identified putative non-catalytic phosphatase domains in all subclasses of the PTP family. The presence of inactive phosphatase domains in all subclasses indicates that they were invented multiple times in evolution. Depending on the domain composition, loss of catalytic activity can result in different consequences for the function of the protein. Inactive single domain phosphatases can still specifically bind substrate and protect it from dephosphorylation by other phosphatases. The inactive domains of tandem phosphatases can be further subdivided. The first class is more conserved, still able to bind phosphorylated tyrosine residues and might recruit multi-phosphorylated substrates for the adjacent active domain. The second has accumulated several variable amino acid substitutions in the catalytic center indicating a complete loss of tyrosine binding capabilities. To study the impact of substitutions in the catalytic center to the evolution of the whole domain, we examined the evolutionary rates for each individual site and compared them between the classes. This analysis revealed a release of evolutionary constraint for multiple sites surrounding the catalytic center only in the second class, emphasizing its difference in function compared to the first class. Furthermore, we found a region of higher conservation common to both domain classes, suggesting a new regulatory center. We discuss the influence of evolutionary forces on the development of the phosphatase domain, which has led to additional functions like the specific protection of phosphorylated tyrosine residues, substrate recruitment and regulation of the catalytic activity of adjacent domains.

Key Words: protein tyrosine phosphatase, anti-phosphatase, signaling enzymes, functional divergence, evolutionary site rates


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