title: Evaluating caveolin interactions: do proteins interact with the caveolin scaffolding domain through a widespread aromatic residue-rich motif?
abstract: Caveolins are coat proteins of caveolae, small flask-shaped pits of the plasma membranes of most cells. Aside from roles in caveolae formation, caveolins recruit, retain and regulate many caveolae-associated signalling molecules. Caveolin-protein interactions are commonly considered to occur between a ∼20 amino acid region within caveolin, the caveolin scaffolding domain (CSD), and an aromatic-rich caveolin binding motif (CBM) on the binding partner (фXфXXXXф, фXXXXфXXф or фXфXXXXфXXф, where ф is an aromatic and X an unspecified amino acid). The CBM resembles a typical linear motif--a short, simple sequence independently evolved many times in different proteins for a specific function. Here we exploit recent improvements in bioinformatics tools and in our understanding of linear motifs to critically examine the role of CBMs in caveolin interactions. We find that sequences conforming to the CBM occur in 30% of human proteins, but find no evidence for their statistical enrichment in the caveolin interactome. Furthermore, sequence- and structure-based considerations suggest that CBMs do not have characteristics commonly associated with true interaction motifs. Analysis of the relative solvent accessible area of putative CBMs shows that the majority of their aromatic residues are buried within the protein and are thus unlikely to interact directly with caveolin, but may instead be important for protein structural stability. Together, these findings suggest that the canonical CBM may not be a common characteristic of caveolin-target interactions and that interfaces between caveolin and targets may be more structurally diverse than presently appreciated.
authors.affiliation: Institute of Integrative Biology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Byrne
authors.forename: Caroline
authors.initials: C
authors.lastname: Dart
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rigden
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D024322:Amino Acids, Aromatic; D022461:Caveolins / Q000737:chemistry* / Q000378:metabolism*; D019295:Computational Biology; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000378:metabolism; D012997:Solvents / Q000737:chemistry
chemical_list: D024322:Amino Acids, Aromatic; D022461:Caveolins; D020543:Proteome; D012997:Solvents