Role of Aromatic Interactions in Amyloid Formation by Peptides Derived from Human Amylin† Export

@article{Tracz_Biochem04, abstract = {doi: 10.1021/bi048812l Numerous polypeptides and proteins form amyloid deposits in vivo or in vitro. The mechanism of amyloid formation is not well-understood particularly in the case where unstructured polypeptides assemble to form amyloid. Aromaticaromatic interactions are known to be important in globular proteins, and the possibility that they might play a key role in amyloid formation has been raised. The results of Ala-scanning experiments on short polypeptides derived from Amylin have suggested that aromatic interactions could be particularly important for this system. Here, we examine a set of Amylin-derived polypeptides in which the single aromatic residue has been substituted with a Leu and Ala. A peptide corresponding to residues 2129 with a Phe-23 to Leu substitution, a free N terminus, and amidated C terminus readily forms amyloid. Shorter peptides derived from the putative minimal amyloid-forming segment of Amylin, residues 2227, also form amyloid when Phe-23 is replaced by Leu. Amyloid formation is more facile when the N terminus is deprotonated and the peptide is uncharged. Substitution of the Phe with Ala results in a peptide that is noticeably less prone to form amyloid. A peptide corresponding to residues 1019 of human Amylin with blocked termini and the sole aromatic residue, Phe-15, substituted by Leu readily forms amyloid. A Phe-15 to Ala substitution reduces significantly the ability to form amyloid. These results indicate that an aromatic residue is not required for amyloid formation in these systems and indicates that other factors such as size, beta-sheet propensity, and hydrophobicity of the side chain in question are also important.}, author = {Tracz, Sylvia M. and Abedini, Andisheh and Driscoll, Miles and Raleigh, Daniel P.}, citeulike-article-id = {3824407}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/bi048812l}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/bi048812l}, day = {1}, doi = {10.1021/bi048812l}, journal = {Biochemistry}, keywords = {amylin, amyloid, aromatic, experimental, peptides}, month = {December}, number = {50}, pages = {15901--15908}, posted-at = {2008-12-26 12:49:57}, priority = {2}, title = {Role of Aromatic Interactions in Amyloid Formation by Peptides Derived from Human Amylin{\dag}}, url = {http://dx.doi.org/10.1021/bi048812l}, volume = {43}, year = {2004} }

TY - JOUR ID - Tracz_Biochem04 L3 - citeulike-article-id:3824407 N2 - doi: 10.1021/bi048812l Numerous polypeptides and proteins form amyloid deposits in vivo or in vitro. The mechanism of amyloid formation is not well-understood particularly in the case where unstructured polypeptides assemble to form amyloid. Aromaticaromatic interactions are known to be important in globular proteins, and the possibility that they might play a key role in amyloid formation has been raised. The results of Ala-scanning experiments on short polypeptides derived from Amylin have suggested that aromatic interactions could be particularly important for this system. Here, we examine a set of Amylin-derived polypeptides in which the single aromatic residue has been substituted with a Leu and Ala. A peptide corresponding to residues 2129 with a Phe-23 to Leu substitution, a free N terminus, and amidated C terminus readily forms amyloid. Shorter peptides derived from the putative minimal amyloid-forming segment of Amylin, residues 2227, also form amyloid when Phe-23 is replaced by Leu. Amyloid formation is more facile when the N terminus is deprotonated and the peptide is uncharged. Substitution of the Phe with Ala results in a peptide that is noticeably less prone to form amyloid. A peptide corresponding to residues 1019 of human Amylin with blocked termini and the sole aromatic residue, Phe-15, substituted by Leu readily forms amyloid. A Phe-15 to Ala substitution reduces significantly the ability to form amyloid. These results indicate that an aromatic residue is not required for amyloid formation in these systems and indicates that other factors such as size, beta-sheet propensity, and hydrophobicity of the side chain in question are also important. IS - 50 JF - Biochemistry EP - 15908 TI - Role of Aromatic Interactions in Amyloid Formation by Peptides Derived from Human Amylin† VL - 43 SP - 15901 KW - amylin KW - amyloid KW - aromatic KW - experimental KW - peptides AU - Tracz, Sylvia AU - Abedini, Andisheh AU - Driscoll, Miles AU - Raleigh, Daniel PY - 2004/12/01/ UR - http://dx.doi.org/10.1021/bi048812l ER -