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

Hayarpi Torosyan, Michael D. Paul, Antoine Forget, Megan Lo, Devan Diwanji, Krzysztof Pawłowski, Nevan J. Krogan, Natalia Jura () and Kliment A. Verba ()
Additional contact information
Hayarpi Torosyan: University of California San Francisco
Michael D. Paul: University of California San Francisco
Antoine Forget: University of California San Francisco
Megan Lo: University of California San Francisco
Devan Diwanji: University of California San Francisco
Krzysztof Pawłowski: University of Texas Southwestern Medical Center
Nevan J. Krogan: University of California San Francisco
Natalia Jura: University of California San Francisco
Kliment A. Verba: University of California San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38864-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38864-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38864-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().