A possible role for pi-stacking in the self-assembly of amyloid fibrils.
Amyloid fibril formation is assumed to be the molecular basis for a variety of diseases of unrelated origin. Despite its fundamental clinical importance, the mechanism of amyloid formation is not fully understood. When we analyzed a variety of short functional fragments from unrelated amyloid-forming proteins, a remarkable occurrence of aromatic residues was observed. The finding of aromatic residues in diverse fragments raises the possibility that pi-pi interactions may play a significant role in the molecular recognition and self-assembly processes that lead to amyloid formation. This is in line with the well-known central role of pi-stacking interactions in self-assembly processes in the fields of chemistry and biochemistry. We speculate that the stacking interactions may provide energetic contribution as well as order and directionality in the self-assembly of amyloid structures. Experimental data regarding amyloid formation and inhibition by short peptide analogs also support our hypothesis. The pi-stacking hypothesis suggests a new approach to understanding the self-assembly mechanism that governs amyloid formation and indicates possible ways to control this process.
Gazit
Ehud
E
Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel Aviv 69978, Israel. ehudg@post.tau.ac.il
D000544:Alzheimer Disease / Q000209:etiology; D000595:Amino Acid Sequence; D024322:Amino Acids, Aromatic / Q000737:chemistry; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface; D005656:Fungal Proteins / Q000737:chemistry; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D058228:Islet Amyloid Polypeptide; D008894:Milk Proteins; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry; D011328:Prions / Q000737:chemistry
D024322:Amino Acids, Aromatic; D000682:Amyloid; D016229:Amyloid beta-Peptides; D000954:Antigens, Surface; D005656:Fungal Proteins; D006023:Glycoproteins; D058228:Islet Amyloid Polypeptide; C098942:MFGE8 protein, human; D008894:Milk Proteins; D010446:Peptide Fragments; D011328:Prions