Caveolin Scaffolding Region and Cholesterol-rich Domains in Membranes

Novel Androstenetriol Interacts with the Mitochondrial Translocator Protein and Controls Steroidogenesis

“…This CRAC motif, defined by the algorithm (L/V)X 1-5 YX 1-5 (R/K), was further described in several other proteins that associate with cholesterol, including CYP11A1 (25), caveolin (29), acetylcholine esterase (31), and the gp41 peptide of the HIV-1 virus (30). Moreover, this motif is very often associated with the functionality of the protein in question.…”

“…Moreover, this motif is very often associated with the functionality of the protein in question. For example, mutation of the CRAC motif in gp41 results in reduced virulence (30), and deletion of the TSPO CRAC motif ablates the ability of the protein to mediate cholesterol uptake when expressed in E. coli (25). NMR spectroscopy of the TSPO CRAC motif demonstrated that the side chains of the motif generated a groove capable of accommodating a cholesterol molecule, with the central tyrosine playing a critical role in cholesterol binding (28).…”

Biogenesis of caveolae: a structural model for caveolin-induced domain formation

“…In this conformation, the diameter of helix ␣2a in combination with the length of the remaining section (helix ␣2b) corresponds to the length of helix ␣3. Interestingly, such in-plane helical membrane anchors have been identified before, and a recent algorithm indicates that the scaffolding domain, which inserts into the interfacial region of the membrane and recruits cholesterol (Arbuzova et al, 2000;Epand et al, 2005), is compatible with such a structure (N. Sapay, Y. Guermeur and G. Deléage, personal communication).…”

“…The experimental evidence that the scaffolding domain participates in membrane interaction (Arbuzova et al, 2000;Epand et al, 2005) makes the hydrophobic region much longer than the 33-residue intramembrane domain (102-134) originally proposed, essentially eliminating the need for a hairpin structure. Because a second pair of tryptophan residues (W85 and W98) spaced 12 residues apart is present, one could assign residues 81-101 to a single outbound helix ␣2 (not shown in Fig.…”

“…The CRAC motif in caveolin-1 (residues 94 to 101) has not been directly implicated in a simple 1:1 interaction with cholesterol. A comparison of three peptides derived from this region of caveolin-1, one corresponding to the entire scaffolding domain, a second shorter peptide containing the CRAC motif (VTKYWFYR) and a third that does not (KYWFYR) (Epand et al, 2005), shows that the two CRAC-motif-containing peptides associate with liposomes, insert into the membrane and promote segregation of cholesterol into domains (Epand et al, 2005). The sequestered cholesterol is present in crystalline complexes, which indicates that the enrichment is not a result of peptide-cholesterol binding but to an alteration of membrane properties that allows cholesterol enrichment.…”