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.
Highlights
Caveolins are a family of cholesterol-binding membrane proteins that coat the intracellular surface of caveolae, small flask-shaped pits (50–100 nm in diameter) that form at the plasma membrane of most cells [1,2,3,4]
Interaction with caveolin, which appears to be important in protein recruitment to caveolar domains and the formation of microenvironments rich in interacting signalling molecules, is commonly believed to be mediated via a,20 amino acid N-terminal region on the caveolin molecule known as the caveolin scaffolding domain (CSD) and an aromatic-rich caveolin binding motif (CBM) on the associated protein [6,7]
We examine the relative solvent accessible area (RSA) of the CBM aromatic residues for Cav-1 interaction partners in solved crystal structures and homology models to assess the likelihood that the conserved aromatics are available for direct binding of proteins
Summary
Caveolins are a family of cholesterol-binding membrane proteins (caveolin-1, -2 and -3) that coat the intracellular surface of caveolae, small flask-shaped pits (50–100 nm in diameter) that form at the plasma membrane of most cells [1,2,3,4]. Aside from roles in caveolae formation and stability, caveolins interact with many caveolae-localized signalling molecules including heterotrimeric G proteins, Src family tyrosine kinases, phosphoinositide 3-kinase, integrins, epidermal growth factor receptor (EGFR), H-Ras, endothelial nitric oxide synthase (eNOS) and a number of ion channels [3,5]. Association with caveolin typically suppresses activity in the targeted protein [6,7], suggesting that recruitment to caveolae might hamper and not enhance signalling efficiency (the so-called ‘caveolar paradox’). This paradox has been largely resolved for eNOS whereby interaction with caveolin under basal conditions maintains an inactive enzyme and compartmentalization of eNOS in caveolae ensures a rapid response upon stimulation [8].
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