Reches Meital, Porat Yair, Gazit Ehud
Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel.
J Biol Chem. 2002 Sep 20;277(38):35475-80. doi: 10.1074/jbc.M206039200. Epub 2002 Jul 2.
The process of amyloid fibril formation by the human calcitonin hormone is associated with medullary thyroid carcinoma. Based on the effect of pH on the fibrillization of human calcitonin, the analysis of conformationally constrained analogues of the hormone, and our suggestion regarding the role of aromatic residues in the process of amyloid fibril formation, we studied the ability of a short aromatic charged peptide fragment of calcitonin (NH(2)-DFNKF-COOH) to form amyloid fibrils. Here, using structural and biophysical analysis, we clearly demonstrate the ability of this short peptide to form well ordered amyloid fibrils. A shorter truncated tetrapeptide, NH(2)-DFNK-COOH, also formed fibrils albeit less ordered than those formed by the pentapeptide. We could not detect amyloid fibril formation by the NH(2)-FNKF-COOH tetrapeptide, the NH(2)-DFN-COOH tripeptide, or the NH(2)-DANKA-COOH phenylalanine to the alanine analogue of the pentapeptide. The formation of amyloid fibrils by rather hydrophilic peptides is quite striking, because it was speculated that hydrophobic interactions might play a key role in amyloid formation. This is the first reported case of fibril formation by a peptide as short as a tetrapeptide and one of very few cases of amyloid formation by pentapeptides. Because the aromatic nature seems to be the only common property of the various very short amyloid-forming peptides, it further supports our hypothesis on the role of aromatic interactions in the process of amyloid fibril formation.
人降钙素激素形成淀粉样纤维的过程与甲状腺髓样癌相关。基于pH对人降钙素纤维化的影响、对该激素构象受限类似物的分析以及我们关于芳香族残基在淀粉样纤维形成过程中作用的推测，我们研究了降钙素的一个短的芳香族带电肽片段（NH(2)-DFNKF-COOH）形成淀粉样纤维的能力。在此，通过结构和生物物理分析，我们清楚地证明了这个短肽形成高度有序淀粉样纤维的能力。一个更短的截短四肽NH(2)-DFNK-COOH也形成了纤维，尽管其有序程度低于五肽形成的纤维。我们未检测到NH(2)-FNKF-COOH四肽、NH(2)-DFN-COOH三肽或五肽的NH(2)-DANKA-COOH苯丙氨酸到丙氨酸类似物形成淀粉样纤维。相当亲水的肽形成淀粉样纤维这一现象颇为引人注目，因为据推测疏水相互作用可能在淀粉样形成中起关键作用。这是首次报道短至四肽的肽形成纤维的案例，也是五肽形成淀粉样的极少数案例之一。由于芳香族性质似乎是各种极短的淀粉样形成肽唯一的共同特性，这进一步支持了我们关于芳香族相互作用在淀粉样纤维形成过程中作用的假说。
