PTP-central: a comprehensive resource of protein tyrosine phosphatases in eukaryotic genomes.

Reversible tyrosine phosphorylation is a fundamental signaling mechanism controlling a diversity of cellular processes. Whereas protein tyrosine kinases have long been implicated in many diseases, aberrant protein tyrosine phosphatase (PTP) activity is also increasingly being associated with a wide spectrum of conditions. PTPs are now regarded as key regulators of biochemical processes instead of simple "off" switches operating in tyrosine kinase signaling pathways. Despite the central importance that PTPs play in the cell's biochemistry, the tyrosine phosphatomes of most species remain uncharted. Here we present a highly sensitive and specific sequence-based method for the automatic classification of PTPs. As proof of principle we re-annotated the human tyrosine phosphatome, and discovered four new PTP genes that had not been reported before. Our method and the predicted tyrosine phosphatomes of 65 eukaryotic genomes are accessible online through the user-friendly PTP-central resource (http://www.PTP-central.org/), where users can also submit their own sequences for prediction. PTP-central is a comprehensive and continually developing resource that currently integrates the predicted tyrosine phosphatomes with structural data and genetic association disease studies, as well as homology relationships. PTP-central thus fills an important void for the systematic study of PTPs, both in model organisms and from an evolutionary perspective.

The repertoires of ubiquitinating and deubiquitinating enzymes in eukaryotic genomes.

Reversible protein ubiquitination regulates virtually all known cellular activities. Here, we present a quantitatively evaluated and broadly applicable method to predict eukaryotic ubiquitinating enzymes (UBE) and deubiquitinating enzymes (DUB) and its application to 50 distinct genomes belonging to four of the five major phylogenetic supergroups of eukaryotes: unikonts (including metazoans, fungi, choanozoa, and amoebozoa), excavates, chromalveolates, and plants. Our method relies on a collection of profile hidden Markov models, and we demonstrate its superior performance (coverage and classification accuracy >99%) by identifying approximately 25% and approximately 35% additional UBE and DUB genes in yeast and human, which had not been reported before. In yeast, we predict 85 UBE and 24 DUB genes, for 814 UBE and 107 DUB genes in the human genome. Most UBE and DUB families are present in all eukaryotic lineages, with plants and animals harboring massively enlarged repertoires of ubiquitin ligases. Unicellular organisms, on the other hand, typically harbor less than 300 UBEs and less than 40 DUBs per genome. Ninety-one UBE/DUB genes are orthologous across all four eukaryotic supergroups, and these likely represent a primordial core of enzymes of the ubiquitination system probably dating back to the first eukaryotes approximately 2 billion years ago. Our genome-wide predictions are available through the Database of Ubiquitinating and Deubiquitinating Enzymes (www.DUDE-db.org), where users can also perform advanced sequence and phylogenetic analyses and submit their own predictions.