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Cotranslational interaction of human EBP50 and ezrin overcomes masked binding site during complex assembly
Multiprotein assemblages are the intracellular workhorses of many physiological processes. Assembly of constituents into complexes can be driven by stochastic, domain-dependent, posttranslational events in which mature, folded proteins specifically interact. However, inaccessibility of interacting s...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851480/ https://www.ncbi.nlm.nih.gov/pubmed/35140182 http://dx.doi.org/10.1073/pnas.2115799119 |
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author | Khan, Krishnendu Long, Briana Baleanu-Gogonea, Camelia Gogonea, Valentin Deshpande, Gauravi M. Vasu, Kommireddy Fox, Paul L. |
author_facet | Khan, Krishnendu Long, Briana Baleanu-Gogonea, Camelia Gogonea, Valentin Deshpande, Gauravi M. Vasu, Kommireddy Fox, Paul L. |
author_sort | Khan, Krishnendu |
collection | PubMed |
description | Multiprotein assemblages are the intracellular workhorses of many physiological processes. Assembly of constituents into complexes can be driven by stochastic, domain-dependent, posttranslational events in which mature, folded proteins specifically interact. However, inaccessibility of interacting surfaces in mature proteins (e.g., due to “buried” domains) can obstruct complex formation. Mechanisms by which multiprotein complex constituents overcome topological impediments remain enigmatic. For example, the heterodimeric complex formed by EBP50 and ezrin must address this issue as the EBP50-interacting domain in ezrin is obstructed by a self-interaction that occupies the EBP50 binding site. Here, we show that the EBP50-ezrin complex is formed by a cotranslational mechanism in which the C terminus of mature, fully formed EBP50 binds the emerging, ribosome-bound N-terminal FERM domain of ezrin during EZR mRNA translation. Consistent with this observation, a C-terminal EBP50 peptide mimetic reduces the cotranslational interaction and abrogates EBP50-ezrin complex formation. Phosphorylation of EBP50 at Ser(339) and Ser(340) abrogates the cotranslational interaction and inhibits complex formation. In summary, we show that the function of eukaryotic mRNA translation extends beyond “simple” generation of a linear peptide chain that folds into a tertiary structure, potentially for subsequent complex assembly; importantly, translation can facilitate interactions with sterically inaccessible domains to form functional multiprotein complexes. |
format | Online Article Text |
id | pubmed-8851480 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-88514802022-08-10 Cotranslational interaction of human EBP50 and ezrin overcomes masked binding site during complex assembly Khan, Krishnendu Long, Briana Baleanu-Gogonea, Camelia Gogonea, Valentin Deshpande, Gauravi M. Vasu, Kommireddy Fox, Paul L. Proc Natl Acad Sci U S A Biological Sciences Multiprotein assemblages are the intracellular workhorses of many physiological processes. Assembly of constituents into complexes can be driven by stochastic, domain-dependent, posttranslational events in which mature, folded proteins specifically interact. However, inaccessibility of interacting surfaces in mature proteins (e.g., due to “buried” domains) can obstruct complex formation. Mechanisms by which multiprotein complex constituents overcome topological impediments remain enigmatic. For example, the heterodimeric complex formed by EBP50 and ezrin must address this issue as the EBP50-interacting domain in ezrin is obstructed by a self-interaction that occupies the EBP50 binding site. Here, we show that the EBP50-ezrin complex is formed by a cotranslational mechanism in which the C terminus of mature, fully formed EBP50 binds the emerging, ribosome-bound N-terminal FERM domain of ezrin during EZR mRNA translation. Consistent with this observation, a C-terminal EBP50 peptide mimetic reduces the cotranslational interaction and abrogates EBP50-ezrin complex formation. Phosphorylation of EBP50 at Ser(339) and Ser(340) abrogates the cotranslational interaction and inhibits complex formation. In summary, we show that the function of eukaryotic mRNA translation extends beyond “simple” generation of a linear peptide chain that folds into a tertiary structure, potentially for subsequent complex assembly; importantly, translation can facilitate interactions with sterically inaccessible domains to form functional multiprotein complexes. National Academy of Sciences 2022-02-09 2022-02-15 /pmc/articles/PMC8851480/ /pubmed/35140182 http://dx.doi.org/10.1073/pnas.2115799119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Khan, Krishnendu Long, Briana Baleanu-Gogonea, Camelia Gogonea, Valentin Deshpande, Gauravi M. Vasu, Kommireddy Fox, Paul L. Cotranslational interaction of human EBP50 and ezrin overcomes masked binding site during complex assembly |
title | Cotranslational interaction of human EBP50 and ezrin overcomes masked binding site during complex assembly |
title_full | Cotranslational interaction of human EBP50 and ezrin overcomes masked binding site during complex assembly |
title_fullStr | Cotranslational interaction of human EBP50 and ezrin overcomes masked binding site during complex assembly |
title_full_unstemmed | Cotranslational interaction of human EBP50 and ezrin overcomes masked binding site during complex assembly |
title_short | Cotranslational interaction of human EBP50 and ezrin overcomes masked binding site during complex assembly |
title_sort | cotranslational interaction of human ebp50 and ezrin overcomes masked binding site during complex assembly |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851480/ https://www.ncbi.nlm.nih.gov/pubmed/35140182 http://dx.doi.org/10.1073/pnas.2115799119 |
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