A search method for homologs of small proteins. Ubiquitin-like proteins in prokaryotic cells?

The question of protein homology versus analogy arises whenproteins share a common function or a common structural foldwithout any statistically significant amino acid sequence similarity.Even though two or more proteins do not have similar sequencesbut share a common fold and the same or closely related function,they are assumed to be homologs, descendant from a common ancestor.The problem of homolog identification is compounded in the caseof proteins of 100 or less amino acids. This is due to a limitednumber of basic single domain folds and to a likelihood of identifyingby chance sequence similarity. The latter arises from two conditions:first, any search of the currently very large protein databaseis likely to identify short regions of chance match; secondly,a direct sequence comparison among a small set of short proteinssharing a similar fold can detect many similar patterns of hydrophobicityeven if proteins do not descend from a common ancestor. In aneffort to identify distant homologs of the many ubiquitin proteins,we have developed a combined structure and sequence similarityapproach that attempts to overcome the above limitations ofhomolog identification. This approach results in the identificationof 90 probable ubiquitin-related proteins, including examplesfrom the two prokaryotic domains of life, Archaea and Bacteria. Received December 1, 2002; revised October 22, 2003; accepted October 24, 2003