Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins.
The V3 loop of the human immunodeficiency virus (HIV)-1 surface envelope glycoprotein gp120 is a sphingolipid-binding domain mediating the attachment of HIV-1 to plasma membrane microdomains (rafts). Sphingolipid-induced conformational changes in gp120 are required for HIV-1 fusion. Galactosylceramide and sphingomyelin have been detected in highly purified preparations of prion rods, suggesting that the prion protein (PrP) may interact with selected sphingolipids. Moreover, a major conformational transition of the Alzheimer beta-amyloid peptide has been observed upon interaction with sphingolipid-containing membranes. Structure similarity searches with the combinatorial extension method revealed the presence of a V3-like domain in the human prion protein PrP and in the Alzheimer beta-amyloid peptide. In each case, synthetic peptides derived from the predicted V3-like domain were found to interact with monomolecular films of galactosylceramide and sphingomyelin at the air-water interface. The V3-like domain of PrP is a disulfide-linked loop (Cys(179)-Cys(214)) that includes the E200K mutation site associated with familial Creutzfeldt-Jakob disease. This mutation abrogated sphingomyelin recognition. The identification of a common sphingolipid-binding motif in gp120, PrP, and beta-amyloid peptide underscores the role of lipid rafts in the pathogenesis of HIV-1, Alzheimer, and prion diseases and may provide new therapeutic strategies.
Mahfoud
Radhia
R
Institut Méditerranéen de Recherche en Nutrition, Unité Mixte de Recherche-Institut National de la recherche Agronomique 1111, Faculté des Sciences St-Jérôme, 13397 Marseille Cedex 20, France.
Garmy
Nicolas
N
Maresca
Marc
M
Yahi
Nouara
N
Puigserver
Antoine
A
Fantini
Jacques
J
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D015497:HIV-1 / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding; D013107:Sphingolipids / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
D011328:Prions; D013107:Sphingolipids; D014764:Viral Proteins