The role of protein sequence and amino acid composition in amyloid formation: scrambling and backward reading of IAPP amyloid fibrils.
The specific functional structure of natural proteins is determined by the way in which amino acids are sequentially connected in the polypeptide. The tight sequence/structure relationship governing protein folding does not seem to apply to amyloid fibril formation because many proteins without any sequence relationship have been shown to assemble into very similar β-sheet-enriched structures. Here, we have characterized the aggregation kinetics, seeding ability, morphology, conformation, stability, and toxicity of amyloid fibrils formed by a 20-residue domain of the islet amyloid polypeptide (IAPP), as well as of a backward and scrambled version of this peptide. The three IAPP peptides readily aggregate into ordered, β-sheet-enriched, amyloid-like fibrils. However, the mechanism of formation and the structural and functional properties of aggregates formed from these three peptides are different in such a way that they do not cross-seed each other despite sharing a common amino acid composition. The results confirm that, as for globular proteins, highly specific polypeptide sequential traits govern the assembly pathway, final fine structure, and cytotoxic properties of amyloid conformations.
Sabaté
Raimon
R
Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
Espargaró
Alba
A
de Groot
Natalia S
NS
Valle-Delgado
Juan José
JJ
Fernàndez-Busquets
Xavier
X
Ventura
Salvador
S
D000465:Algorithms; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D000682:Amyloid / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics* / Q000633:toxicity; D002460:Cell Line; D004396:Coloring Agents; D003224:Congo Red; D006801:Humans; D066298:In Vitro Techniques; D058228:Islet Amyloid Polypeptide / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics* / Q000633:toxicity; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics
D000596:Amino Acids; D000682:Amyloid; D004396:Coloring Agents; D058228:Islet Amyloid Polypeptide; D003224:Congo Red