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Stepwise design of pseudosymmetric protein hetero-oligomers

Pseudosymmetric hetero-oligomers with three or more unique subunits with overall structural (but not sequence) symmetry play key roles in biology, and systematic approaches for generating such proteins de novo would provide new routes to controlling cell signaling and designing complex protein mater...

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Autores principales: Kibler, Ryan D., Lee, Sangmin, Kennedy, Madison A., Wicky, Basile I. M., Lai, Stella M., Kostelic, Marius M., Li, Xinting, Chow, Cameron M., Carter, Lauren, Wysocki, Vicki H., Stoddard, Barry L., Baker, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104133/
https://www.ncbi.nlm.nih.gov/pubmed/37066191
http://dx.doi.org/10.1101/2023.04.07.535760
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author Kibler, Ryan D.
Lee, Sangmin
Kennedy, Madison A.
Wicky, Basile I. M.
Lai, Stella M.
Kostelic, Marius M.
Li, Xinting
Chow, Cameron M.
Carter, Lauren
Wysocki, Vicki H.
Stoddard, Barry L.
Baker, David
author_facet Kibler, Ryan D.
Lee, Sangmin
Kennedy, Madison A.
Wicky, Basile I. M.
Lai, Stella M.
Kostelic, Marius M.
Li, Xinting
Chow, Cameron M.
Carter, Lauren
Wysocki, Vicki H.
Stoddard, Barry L.
Baker, David
author_sort Kibler, Ryan D.
collection PubMed
description Pseudosymmetric hetero-oligomers with three or more unique subunits with overall structural (but not sequence) symmetry play key roles in biology, and systematic approaches for generating such proteins de novo would provide new routes to controlling cell signaling and designing complex protein materials. However, the de novo design of protein hetero-oligomers with three or more distinct chains with nearly identical structures is a challenging problem because it requires the accurate design of multiple protein-protein interfaces simultaneously. Here, we describe a divide-and-conquer approach that breaks the multiple-interface design challenge into a set of more tractable symmetric single-interface redesign problems, followed by structural recombination of the validated homo-oligomers into pseudosymmetric hetero-oligomers. Starting from de novo designed circular homo-oligomers composed of 9 or 24 tandemly repeated units, we redesigned the inter-subunit interfaces to generate 15 new homo-oligomers and recombined them to make 17 new hetero-oligomers, including ABC heterotrimers, A2B2 heterotetramers, and A3B3 and A2B2C2 heterohexamers which assemble with high structural specificity. The symmetric homo-oligomers and pseudosymmetric hetero-oligomers generated for each system share a common backbone, and hence are ideal building blocks for generating and functionalizing larger symmetric assemblies.
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spelling pubmed-101041332023-04-15 Stepwise design of pseudosymmetric protein hetero-oligomers Kibler, Ryan D. Lee, Sangmin Kennedy, Madison A. Wicky, Basile I. M. Lai, Stella M. Kostelic, Marius M. Li, Xinting Chow, Cameron M. Carter, Lauren Wysocki, Vicki H. Stoddard, Barry L. Baker, David bioRxiv Article Pseudosymmetric hetero-oligomers with three or more unique subunits with overall structural (but not sequence) symmetry play key roles in biology, and systematic approaches for generating such proteins de novo would provide new routes to controlling cell signaling and designing complex protein materials. However, the de novo design of protein hetero-oligomers with three or more distinct chains with nearly identical structures is a challenging problem because it requires the accurate design of multiple protein-protein interfaces simultaneously. Here, we describe a divide-and-conquer approach that breaks the multiple-interface design challenge into a set of more tractable symmetric single-interface redesign problems, followed by structural recombination of the validated homo-oligomers into pseudosymmetric hetero-oligomers. Starting from de novo designed circular homo-oligomers composed of 9 or 24 tandemly repeated units, we redesigned the inter-subunit interfaces to generate 15 new homo-oligomers and recombined them to make 17 new hetero-oligomers, including ABC heterotrimers, A2B2 heterotetramers, and A3B3 and A2B2C2 heterohexamers which assemble with high structural specificity. The symmetric homo-oligomers and pseudosymmetric hetero-oligomers generated for each system share a common backbone, and hence are ideal building blocks for generating and functionalizing larger symmetric assemblies. Cold Spring Harbor Laboratory 2023-04-07 /pmc/articles/PMC10104133/ /pubmed/37066191 http://dx.doi.org/10.1101/2023.04.07.535760 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Kibler, Ryan D.
Lee, Sangmin
Kennedy, Madison A.
Wicky, Basile I. M.
Lai, Stella M.
Kostelic, Marius M.
Li, Xinting
Chow, Cameron M.
Carter, Lauren
Wysocki, Vicki H.
Stoddard, Barry L.
Baker, David
Stepwise design of pseudosymmetric protein hetero-oligomers
title Stepwise design of pseudosymmetric protein hetero-oligomers
title_full Stepwise design of pseudosymmetric protein hetero-oligomers
title_fullStr Stepwise design of pseudosymmetric protein hetero-oligomers
title_full_unstemmed Stepwise design of pseudosymmetric protein hetero-oligomers
title_short Stepwise design of pseudosymmetric protein hetero-oligomers
title_sort stepwise design of pseudosymmetric protein hetero-oligomers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104133/
https://www.ncbi.nlm.nih.gov/pubmed/37066191
http://dx.doi.org/10.1101/2023.04.07.535760
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