| Structural highlights
Function
PEAK3_HUMAN Probable catalytically inactive kinase (Probable). Interacts with CRK-II and antagonizes CRK-II-signaling. Prevents the formation of CRK-II-dependent membrane ruffling and lamellipodia-like extensions (PubMed:31311869).[1] [2]
Publication Abstract from PubMed
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.
Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3.,Torosyan H, Paul MD, Forget A, Lo M, Diwanji D, Pawlowski K, Krogan NJ, Jura N, Verba KA Nat Commun. 2023 Jun 19;14(1):3543. doi: 10.1038/s41467-023-38864-0. PMID:37336883[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lopez ML, Lo M, Kung JE, Dudkiewicz M, Jang GM, Von Dollen J, Johnson JR, Krogan NJ, Pawłowski K, Jura N. PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization. Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15495-15504. PMID:31311869 doi:10.1073/pnas.1906360116
- ↑ Lopez ML, Lo M, Kung JE, Dudkiewicz M, Jang GM, Von Dollen J, Johnson JR, Krogan NJ, Pawłowski K, Jura N. PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization. Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15495-15504. PMID:31311869 doi:10.1073/pnas.1906360116
- ↑ Torosyan H, Paul MD, Forget A, Lo M, Diwanji D, Pawłowski K, Krogan NJ, Jura N, Verba KA. Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3. Nat Commun. 2023 Jun 19;14(1):3543. PMID:37336883 doi:10.1038/s41467-023-38864-0
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