Amyloidogenic hexapeptide fragment of medin: homology to functional islet amyloid polypeptide fragments.
Medin is the main constituent of aortic medial amyloid that occurs in virtually all individuals older than sixty. It is derived from a proteolytic fragment of lactadherin, a mammary epithelial cell expressed glyco-protein that is secreted as part of the milk fat globule membrane. It was previously demonstrated that an octapeptide fragment of medin (NH2-NFGSVQFV-COOH) forms typical well-ordered amyloid fibrils. To obtain further insights into the molecular determinants that mediate this process by such a short peptide fragment, we examined the amyloidogenic potential of its truncated forms and analogues. Our results clearly indicated that a truncated fragment of medin, the hexapeptide, NFGSVQ can form typical amyloid fibrils. A shorter pentapeptide fragment, NFGSV, self-assembled into a gel structure that exhibited a network of fibrous structures. The amyloid forming NFGSVQ hexapeptide is noticeably similar to the short amyloidogenic peptide fragments of the islet amyloid polypeptide (IAPP), NFGAIL and NFLVH. Moreover, the substitution of the phenylalanine residue with either alanine or isoleucine significantly reduced the amyloidogenic potential of the peptide fragment. Taken together, the results are consistent with the assumed role of stacking interactions in the self-assembly processes that lead to the formation of amyloid fibrils. The results are discussed in the context of models for the mechanism of fibril formation and ways to design inhibitors.
Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, 69978, Israel.
Meital
M
Reches
Ehud
E
Gazit
D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000682:Amyloid / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008894:Milk Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*
D000682:Amyloid; D000954:Antigens, Surface; D006023:Glycoproteins; C098942:MFGE8 protein, human; D008894:Milk Proteins; D010446:Peptide Fragments