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Extended β-Strands Contribute to Reversible Amyloid Formation

Murray, Kevin A. and Evans, Declan and Hughes, Michael P. and Sawaya, Michael R. and Hu, Carolyn J. and Houk, Kendall N. and Eisenberg, David (2022) Extended β-Strands Contribute to Reversible Amyloid Formation. ACS Nano, 16 (2). pp. 2154-2163. ISSN 1936-0851. doi:10.1021/acsnano.1c08043. https://resolver.caltech.edu/CaltechAUTHORS:20220208-948240000

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Abstract

The assembly of proteins into fibrillar amyloid structures was once considered to be pathologic and essentially irreversible. Recent studies reveal amyloid-like structures that form reversibly, derived from protein low-complexity domains which function in cellular metabolism. Here, by comparing atomic-level structures of reversible and irreversible amyloid fibrils, we find that the β-sheets of reversible fibrils are enriched in flattened (as opposed to pleated) β-sheets formed by stacking of extended β-strands. Quantum mechanical calculations show that glycine residues favor extended β-strands which may be stabilized by intraresidue interactions between the amide proton and the carbonyl oxygen, known as C5 hydrogen-bonds. Larger residue side chains favor shorter strands and pleated sheets. These findings highlight a structural element that may regulate reversible amyloid assembly.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acsnano.1c08043DOIArticle
ORCID:
AuthorORCID
Murray, Kevin A.0000-0003-1969-7701
Sawaya, Michael R.0000-0003-0874-9043
Hu, Carolyn J.0000-0001-6218-4034
Houk, Kendall N.0000-0002-8387-5261
Eisenberg, David0000-0003-2432-5419
Additional Information:© 2022 American Chemical Society. Received: September 13, 2021; Accepted: January 14, 2022; Published: February 8, 2022. KAM is supported by the UCLA-Caltech Medical Scientist Training Program (GM08042). KAM and DE are supported by the UCLA Chemistry-Biology Interface training grant (USPHS National Research Service Award 5T32GM008496). We thank Duilio Cascio and the UCLA DOE Macromolecular Crystallization Core facility. Funding for this work is provided by the Howard Hughes Medical Institute and NIH. This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P30 GM124165). The Eiger 16M detector on the 24-ID-E beamline is funded by a NIH-ORIP HEI grant (S10OD021527). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We also thank NIH AG 054022, AG070895, and AG 048120 and DOE DE-FC02-02ER63421 for support. Author Contributions. Project was conceived and designed by KAM and DEisenberg. KAM performed structure analysis with assistance from CJH. DEvans carried out all quantum calculations, with guidance from KNH. MPH wrote script to calculate atomic distances. MPH and MRS crystallized and determined the Nup54 structure. Manuscript was written by KAM and DEisenberg with contributions from all other authors. All images for main text and supplemental figures were created in their entirety by KAM and DEvans. KAM and DEvans contributed equally. The authors declare the following competing financial interest(s): DSE is a SAB chair and equity holder of ADRx, Inc.
Funders:
Funding AgencyGrant Number
NIH Predoctoral FellowshipGM08042
NIH Predoctoral Fellowship5T32GM008496
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIHP30 GM124165
NIHS10OD021527
Department of Energy (DOE)DE-AC02-06CH11357
NIHAG 054022
NIHAG 070895
NIHAG 048120
Department of Energy (DOE)DE-FC02-02ER63421
Subject Keywords:amyloid structure; C5 hydrogen-bond; DFT; X-ray crystallography; reversible amyloid
Issue or Number:2
DOI:10.1021/acsnano.1c08043
Record Number:CaltechAUTHORS:20220208-948240000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220208-948240000
Official Citation:Extended β-Strands Contribute to Reversible Amyloid Formation. Kevin A. Murray, Declan Evans, Michael P. Hughes, Michael R. Sawaya, Carolyn J. Hu, Kendall N. Houk, and David Eisenberg. ACS Nano 2022 16 (2), 2154-2163; DOI: 10.1021/acsnano.1c08043
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:113333
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:08 Feb 2022 20:32
Last Modified:10 Mar 2022 20:32

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