Fingerprinting G-protein-coupled receptors

Abstract

Recently we reported the design of a discriminating fingerprint for rhodopsin-like G-protein-coupled receptors (GPCRs). The fingerprint encodes the seven putative membrane-spanning motifs and was potently diagnostic of all GPCRs (52 in all) in version 8.1 of the OWL composite sequence database, readily distinguishing them from all other integral membrane proteins. With a 3-fold increase in the size of OWL, the fingerprint has been updated and now finds 332 receptors that match all the motifs. The situation, however, has grown in complexity: 61 sequences make imperfect matches with the fingerprint, yielding a total of 393 'hits'. The bulk of the partial hits are olfactory receptors: these appear to fall into discrete subfamilies in which one or more of the transmembrane motifs are either poorly matched or are not matched at all. These results are supported by preliminary phylogenetic analyses, which show the olfactory and various other partial matches clustering away from the main body of true hits. The approach has provided a powerful diagnostic tool for identifying GPCRs, and results are consistent with previous observations that the pheromone, cAMP and secretin-like receptors belong to separate families--these bear their own unique sequence fingerprints by which they may be distinguished from the rhodopsin-like superfamily.