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Modulating the Folding Landscape of Superoxide Dismutase 1 with Targeted Molecular Binders

Bunck, David N. and Atsavapranee, Beatriz and Museth, Anna K. and VanderVelde, David and Heath, James R. (2018) Modulating the Folding Landscape of Superoxide Dismutase 1 with Targeted Molecular Binders. Angewandte Chemie International Edition, 57 (21). pp. 6212-6215. ISSN 1433-7851. PMCID PMC6295353. https://resolver.caltech.edu/CaltechAUTHORS:20180412-142012478

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Abstract

Amyotrophic lateral sclerosis, or Lou Gehrig's disease, is characterized by motor neuron death with average survival times of 2 ‐ 5 years. One cause of this disease is the misfolding of superoxide dismutase 1 (SOD1), a protein whose stability and aggregation propensity are affected by point mutations spanning the protein. Here, we use an epitope‐specific, high‐throughput screen to identify peptides that both stabilize the native conformation of SOD1 as well as accelerate its folding by 2.5‐fold. Ligands targeted to the electrostatic loop on the periphery of the protein tightened the non‐metalated structure and accelerated its folding. This strategy may be useful for fundamental studies of protein energy landscapes as well as designing new classes of therapeutics.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/anie.201802269DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295353/PubMed CentralArticle
ORCID:
AuthorORCID
Heath, James R.0000-0001-5356-4385
Additional Information:© 2018 Wiley‐VCH Verlag GmbH. Manuscript accepted: 10 April 2018; Manuscript revised: 05 April 2018; Manuscript received: 20 February 2018. This work was supported by the Institute for Collaborative Biotechnologies (W911NF-09-D-0001) from the U.S. Army Research Office and the Jean Perkins Foundation. Instrumentation was provided by the Center for Catalysis and Chemical Synthesis, the Protein Expression Center, and the Center for the Chemistry of Cellular Signaling at Caltech. D.N.B acknowledges a NIH Postdoctoral Fellowship. B.A. acknowledges Mary Vodopia and Laurence J. Stuppy SURF fellowships. J.R.H. is a founder and board member of Indi Molecular, which is seeking to commercialize the PCC technology.
Funders:
Funding AgencyGrant Number
Army Research Office (ARO)W911NF-09-D-0001
Jean Perkins FoundationUNSPECIFIED
NIH Postdoctoral FellowshipUNSPECIFIED
Caltech Summer Undergraduate Research Fellowship (SURF)UNSPECIFIED
Subject Keywords:protein folding • neurodegenerative disease • peptides • one-bead one-compound library • high-throughput screening
Issue or Number:21
PubMed Central ID:PMC6295353
Record Number:CaltechAUTHORS:20180412-142012478
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180412-142012478
Official Citation:D. N. Bunck, B. Atsavapranee, A. K. Museth, D. VanderVelde, J. R. Heath, Angew. Chem. Int. Ed. 2018, 57, 6212
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85793
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:12 Apr 2018 21:32
Last Modified:03 Oct 2019 19:35

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