The ubiquitin superfamily: members, features, and phylogenies.

The ubiquitin superfamily is a rich repository of small, conserved, functionally unique, and important proteins. Its member proteins fold simply and similarly, with kinetic and thermodynamic ease (Sorenson, J. M.; Head-Gordon, T. Toward minimalist models of larger proteins: A ubiquitin-like protein. Proteins 2002, 46, 368-379). They have been implicated in numerous cancers, neurodegenerations, inflammations, and various disorders affecting signal transduction or protein half-life. These proteins serve the cell generally as portable recognition tags with distinct intracellular roles; indeed, tagging with small protein modifiers has become a new hallmark of post-translational modifications and other signal transduction phenomenon (Finley, D. J. Signal transduction. An alternative to destruction. Nature 2001, 412, 283, 285-286). Because many ubiquitin-like proteins bear similarities in sequence, structure, and function, we gathered protein sequences containing the ubiquitin domain from public databases and created a highly granular and defined protein catabolism database to catalog, summarize, reference, and relate them to their targets and specific ligases (to be described elsewhere). In this paper, we reveal a compilation of proteins possessing the ubiquitin domain. This comprises the first and most important part of our database content. We searched available organismal proteomes for sequence-related members of the ubiquitin superfamily and here present over 200 proteins possessing this domain. These proteins were organized phylogenetically and functionally, thereby defining several new families. To our knowledge, this is the most complete assemblage of ubiquitin domains to date.