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Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3

PEAK pseudokinases are molecular scaffolds which dimerize to regulate cell migration, morphology, and proliferation, as well as cancer progression. The mechanistic role dimerization plays in PEAK scaffolding remains unclear, as there are no structures of PEAKs in complex with their interactors. Here...

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Autores principales: Torosyan, Hayarpi, Paul, Michael D., Forget, Antoine, Lo, Megan, Diwanji, Devan, Pawłowski, Krzysztof, Krogan, Nevan J., Jura, Natalia, Verba, Kliment A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10279700/
https://www.ncbi.nlm.nih.gov/pubmed/37336883
http://dx.doi.org/10.1038/s41467-023-38864-0
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author Torosyan, Hayarpi
Paul, Michael D.
Forget, Antoine
Lo, Megan
Diwanji, Devan
Pawłowski, Krzysztof
Krogan, Nevan J.
Jura, Natalia
Verba, Kliment A.
author_facet Torosyan, Hayarpi
Paul, Michael D.
Forget, Antoine
Lo, Megan
Diwanji, Devan
Pawłowski, Krzysztof
Krogan, Nevan J.
Jura, Natalia
Verba, Kliment A.
author_sort Torosyan, Hayarpi
collection PubMed
description PEAK pseudokinases are molecular scaffolds which dimerize to regulate cell migration, morphology, and proliferation, as well as cancer progression. The mechanistic role dimerization plays in PEAK scaffolding remains unclear, as there are no structures of PEAKs in complex with their interactors. Here, we report the cryo-EM structure of dimeric PEAK3 in complex with an endogenous 14-3-3 heterodimer. Our structure reveals an asymmetric binding mode between PEAK3 and 14-3-3 stabilized by one pseudokinase domain and the SHED domain of the PEAK3 dimer. The binding interface contains a canonical phosphosite-dependent primary interaction and a unique secondary interaction not observed in previous structures of 14-3-3/client complexes. Additionally, we show that PKD regulates PEAK3/14-3-3 binding, which when prevented leads to PEAK3 nuclear enrichment and distinct protein-protein interactions. Altogether, our data demonstrate that PEAK3 dimerization forms an unusual secondary interface for 14-3-3 binding, facilitating 14-3-3 regulation of PEAK3 localization and interactome diversity.
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spelling pubmed-102797002023-06-21 Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3 Torosyan, Hayarpi Paul, Michael D. Forget, Antoine Lo, Megan Diwanji, Devan Pawłowski, Krzysztof Krogan, Nevan J. Jura, Natalia Verba, Kliment A. Nat Commun Article PEAK pseudokinases are molecular scaffolds which dimerize to regulate cell migration, morphology, and proliferation, as well as cancer progression. The mechanistic role dimerization plays in PEAK scaffolding remains unclear, as there are no structures of PEAKs in complex with their interactors. Here, we report the cryo-EM structure of dimeric PEAK3 in complex with an endogenous 14-3-3 heterodimer. Our structure reveals an asymmetric binding mode between PEAK3 and 14-3-3 stabilized by one pseudokinase domain and the SHED domain of the PEAK3 dimer. The binding interface contains a canonical phosphosite-dependent primary interaction and a unique secondary interaction not observed in previous structures of 14-3-3/client complexes. Additionally, we show that PKD regulates PEAK3/14-3-3 binding, which when prevented leads to PEAK3 nuclear enrichment and distinct protein-protein interactions. Altogether, our data demonstrate that PEAK3 dimerization forms an unusual secondary interface for 14-3-3 binding, facilitating 14-3-3 regulation of PEAK3 localization and interactome diversity. Nature Publishing Group UK 2023-06-19 /pmc/articles/PMC10279700/ /pubmed/37336883 http://dx.doi.org/10.1038/s41467-023-38864-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Torosyan, Hayarpi
Paul, Michael D.
Forget, Antoine
Lo, Megan
Diwanji, Devan
Pawłowski, Krzysztof
Krogan, Nevan J.
Jura, Natalia
Verba, Kliment A.
Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
title Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
title_full Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
title_fullStr Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
title_full_unstemmed Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
title_short Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
title_sort structural insights into regulation of the peak3 pseudokinase scaffold by 14-3-3
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10279700/
https://www.ncbi.nlm.nih.gov/pubmed/37336883
http://dx.doi.org/10.1038/s41467-023-38864-0
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