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Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs
PDZ domains constitute a large family of modular domains that are well-known for binding C-terminal motifs of target proteins. Some of them also bind to internal PDZ binding motifs (PDZbms), but this aspect of the PDZ interactome is poorly studied. Here we explored internal PDZbm-mediated interactio...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244488/ https://www.ncbi.nlm.nih.gov/pubmed/34235485 http://dx.doi.org/10.1016/j.crstbi.2021.01.001 |
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author | Ali, Muhammad McAuley, Mishal Mariam Lüchow, Susanne Knapp, Stefan Joerger, Andreas C. Ivarsson, Ylva |
author_facet | Ali, Muhammad McAuley, Mishal Mariam Lüchow, Susanne Knapp, Stefan Joerger, Andreas C. Ivarsson, Ylva |
author_sort | Ali, Muhammad |
collection | PubMed |
description | PDZ domains constitute a large family of modular domains that are well-known for binding C-terminal motifs of target proteins. Some of them also bind to internal PDZ binding motifs (PDZbms), but this aspect of the PDZ interactome is poorly studied. Here we explored internal PDZbm-mediated interactions using the PDZ domain of Shank1 as a model. We identified a series of human Shank1 ligands with C-terminal or internal PDZbms using proteomic peptide-phage display, and established that while the consensus sequence of C-terminal ligands is x-T-x-(L/F)–COOH, the consensus of internal PDZbm is exclusively x-T-x-F-x, where x is any amino acid. We found that the affinities of PDZbm interactions are in the low micromolar range. The crystal structure of the complex between Shank1 PDZ and an internal PDZbm revealed that the binding mode of internal PDZbms was similar to that of C-terminal ligands. Pull-down experiments confirmed that both C-terminal and internal PDZbm interactions can occur in the context of full-length proteins. Our study expands the interactome of Shank1 and hints at a largely unexplored interaction space of PDZ domains. |
format | Online Article Text |
id | pubmed-8244488 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-82444882021-07-06 Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs Ali, Muhammad McAuley, Mishal Mariam Lüchow, Susanne Knapp, Stefan Joerger, Andreas C. Ivarsson, Ylva Curr Res Struct Biol Article PDZ domains constitute a large family of modular domains that are well-known for binding C-terminal motifs of target proteins. Some of them also bind to internal PDZ binding motifs (PDZbms), but this aspect of the PDZ interactome is poorly studied. Here we explored internal PDZbm-mediated interactions using the PDZ domain of Shank1 as a model. We identified a series of human Shank1 ligands with C-terminal or internal PDZbms using proteomic peptide-phage display, and established that while the consensus sequence of C-terminal ligands is x-T-x-(L/F)–COOH, the consensus of internal PDZbm is exclusively x-T-x-F-x, where x is any amino acid. We found that the affinities of PDZbm interactions are in the low micromolar range. The crystal structure of the complex between Shank1 PDZ and an internal PDZbm revealed that the binding mode of internal PDZbms was similar to that of C-terminal ligands. Pull-down experiments confirmed that both C-terminal and internal PDZbm interactions can occur in the context of full-length proteins. Our study expands the interactome of Shank1 and hints at a largely unexplored interaction space of PDZ domains. Elsevier 2021-01-05 /pmc/articles/PMC8244488/ /pubmed/34235485 http://dx.doi.org/10.1016/j.crstbi.2021.01.001 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Ali, Muhammad McAuley, Mishal Mariam Lüchow, Susanne Knapp, Stefan Joerger, Andreas C. Ivarsson, Ylva Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs |
title | Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs |
title_full | Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs |
title_fullStr | Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs |
title_full_unstemmed | Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs |
title_short | Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs |
title_sort | integrated analysis of shank1 pdz interactions with c-terminal and internal binding motifs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244488/ https://www.ncbi.nlm.nih.gov/pubmed/34235485 http://dx.doi.org/10.1016/j.crstbi.2021.01.001 |
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