Stability of the N‑Terminal Helix and Its Role in Amyloid Formation of Serum Amyloid A

• Published in: ACS omega Vol. 3; no. 11; pp. 16184 - 16190
• Main Authors: Wang, Wenhua, Xi, Wenhui, Hansmann, Ulrich H. E
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30-11-2018
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.8b02377

Colonic amyloidosis is the result of overexpression of the serum amyloid A (SAA) protein in inflammatory bowel disease or colon cancer. Crucial for amyloid formation are the first ten N-terminal residues, which in the crystal structure are a part of a 27-residue long helix. Here, we study this 27-residue N-terminal region of SAA by a multiexchange variant of replica exchange molecular dynamics. An ensemble of configurations is observed, dominated by three motifs: the single helix of the crystal structure, a helix-turn-helix configurations, and such where the residues 14–27 are the part of a helix but the first 13 residues form an extended and disordered segment that is prone to aggregation. The single point mutation E9A shifts the equilibrium to the latter motif, indicating the importance of interactions involving this residue for the stability of the SAA protein.