This study investigates the interaction between caveolin and its scaffolding domain, a 20-amino acid membrane-proximal region of the cytosolic amino-terminal domain of caveolin. The authors used phage display libraries to identify peptide ligands that bind to this domain, which are rich in aromatic amino acids and exhibit a characteristic spacing. The interaction was further characterized using a known caveolin-interacting protein, G12a, and a synthetic peptide derived from G12a. The results show that this peptide directly interacts with the caveolin-scaffolding domain and competitively inhibits the binding of G12a to the domain. The study also found that the interaction is dependent on the presence of aromatic residues within the peptide ligand. Additionally, the authors identified critical residues within the caveolin-scaffolding domain that are essential for recognizing both peptide and protein ligands. These findings provide insights into the specificity and mechanism of interaction between caveolin and its associated proteins, highlighting the role of the scaffolding domain in organizing and concentrating signaling molecules within caveolae membranes.This study investigates the interaction between caveolin and its scaffolding domain, a 20-amino acid membrane-proximal region of the cytosolic amino-terminal domain of caveolin. The authors used phage display libraries to identify peptide ligands that bind to this domain, which are rich in aromatic amino acids and exhibit a characteristic spacing. The interaction was further characterized using a known caveolin-interacting protein, G12a, and a synthetic peptide derived from G12a. The results show that this peptide directly interacts with the caveolin-scaffolding domain and competitively inhibits the binding of G12a to the domain. The study also found that the interaction is dependent on the presence of aromatic residues within the peptide ligand. Additionally, the authors identified critical residues within the caveolin-scaffolding domain that are essential for recognizing both peptide and protein ligands. These findings provide insights into the specificity and mechanism of interaction between caveolin and its associated proteins, highlighting the role of the scaffolding domain in organizing and concentrating signaling molecules within caveolae membranes.