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Drivers of α-Sheet Formation in Transthyretin under Amyloidogenic Conditions.
Biochemistry 2019; 58(44):4408-4423B

Abstract

Amyloid diseases make up a set of fatal disorders in which proteins aggregate to form fibrils that deposit in tissues throughout the body. Amyloid-associated diseases are challenging to study because amyloid formation occurs on time scales that span several orders of magnitude and involve heterogeneous, interconverting protein conformations. The development of more effective technologies to diagnose and treat amyloid disease requires both a map of the conformations sampled during amyloidogenesis and an understanding of the molecular mechanisms that drive this process. In prior molecular dynamics simulations of amyloid proteins, we observed the formation of a nonstandard type of secondary structure, called α-sheet, that we proposed is associated with the pathogenic conformers in amyloid disease, the soluble oligomers. However, the detailed molecular interactions that drive the conversion to α-sheet remain elusive. Here we use molecular dynamics simulations to interrogate a critical event in transthyretin aggregation, the formation of aggregation-competent, monomeric species. We show that conformational changes in one of the two β-sheets in transthyretin enable solvent molecules and polar side chains to form electrostatic interactions with main-chain peptide groups to facilitate and modulate conversion to α-sheet secondary structure. Our results shed light on the early conformational changes that drive transthyretin toward the α-sheet structure associated with toxicity. Delineation of the molecular events that lead to aggregation at atomic resolution can aid strategies to target the early, critical toxic soluble oligomers.

Authors+Show Affiliations

Department of Bioengineering , University of Washington , Seattle , Washington 98195-5013 , United States.Department of Bioengineering , University of Washington , Seattle , Washington 98195-5013 , United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31609590

Citation

Childers, Matthew Carter, and Valerie Daggett. "Drivers of α-Sheet Formation in Transthyretin Under Amyloidogenic Conditions." Biochemistry, vol. 58, no. 44, 2019, pp. 4408-4423.
Childers MC, Daggett V. Drivers of α-Sheet Formation in Transthyretin under Amyloidogenic Conditions. Biochemistry. 2019;58(44):4408-4423.
Childers, M. C., & Daggett, V. (2019). Drivers of α-Sheet Formation in Transthyretin under Amyloidogenic Conditions. Biochemistry, 58(44), pp. 4408-4423. doi:10.1021/acs.biochem.9b00769.
Childers MC, Daggett V. Drivers of α-Sheet Formation in Transthyretin Under Amyloidogenic Conditions. Biochemistry. 2019 Nov 5;58(44):4408-4423. PubMed PMID: 31609590.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drivers of α-Sheet Formation in Transthyretin under Amyloidogenic Conditions. AU - Childers,Matthew Carter, AU - Daggett,Valerie, Y1 - 2019/10/25/ PY - 2019/10/15/pubmed PY - 2019/10/15/medline PY - 2019/10/15/entrez SP - 4408 EP - 4423 JF - Biochemistry JO - Biochemistry VL - 58 IS - 44 N2 - Amyloid diseases make up a set of fatal disorders in which proteins aggregate to form fibrils that deposit in tissues throughout the body. Amyloid-associated diseases are challenging to study because amyloid formation occurs on time scales that span several orders of magnitude and involve heterogeneous, interconverting protein conformations. The development of more effective technologies to diagnose and treat amyloid disease requires both a map of the conformations sampled during amyloidogenesis and an understanding of the molecular mechanisms that drive this process. In prior molecular dynamics simulations of amyloid proteins, we observed the formation of a nonstandard type of secondary structure, called α-sheet, that we proposed is associated with the pathogenic conformers in amyloid disease, the soluble oligomers. However, the detailed molecular interactions that drive the conversion to α-sheet remain elusive. Here we use molecular dynamics simulations to interrogate a critical event in transthyretin aggregation, the formation of aggregation-competent, monomeric species. We show that conformational changes in one of the two β-sheets in transthyretin enable solvent molecules and polar side chains to form electrostatic interactions with main-chain peptide groups to facilitate and modulate conversion to α-sheet secondary structure. Our results shed light on the early conformational changes that drive transthyretin toward the α-sheet structure associated with toxicity. Delineation of the molecular events that lead to aggregation at atomic resolution can aid strategies to target the early, critical toxic soluble oligomers. SN - 1520-4995 UR - https://www.unboundmedicine.com/medline/citation/31609590/Drivers_of_α-sheet_formation_in_transthyretin_under_amyloidogenic_conditions L2 - https://dx.doi.org/10.1021/acs.biochem.9b00769 DB - PRIME DP - Unbound Medicine ER -