ArticleThe journal of physical chemistry. B2018
Calmodulin (CaM) Activates PI3Kα by Targeting the "Soft" CaM-Binding Motifs in Both the nSH2 and cSH2 Domains of p85α.
Article in The journal of physical chemistry. B, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- New Insights into the Regulation of mTOR Signaling via CaInternational journal of molecular sciences · 2023Review
- The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia.Biophysical journal · 2022Article
- The mechanism of activation of MEK1 by B-Raf and KSR1.Cellular and molecular life sciences : CMLS · 2022Article
- Mechanism of activation and the rewired network: New drug design concepts.Medicinal research reviews · 2022Review
- Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase.Frontiers in molecular biosciences · 2022Article
- Ras isoform-specific expression, chromatin accessibility, and signaling.Biophysical reviews · 2021Review
- The structural basis of Akt PH domain interaction with calmodulin.Biophysical journal · 2021Article
- The mechanism of activation of monomeric B-Raf V600E.Computational and structural biotechnology journal · 2021Article
- Structural Aspects and Prediction of Calmodulin-Binding Proteins.International journal of molecular sciences · 2020Review
- The Structural Basis of the Farnesylated and Methylated KRas4B Interaction with Calmodulin.Structure (London, England : 1993) · 2019Article
- The structural basis for Ras activation of PI3Kα lipid kinase.Physical chemistry chemical physics : PCCP · 2019Article
- Autoinhibition in Ras effectors Raf, PI3Kα, and RASSF5: a comprehensive review underscoring the challenges in pharmacological intervention.Biophysical reviews · 2018Review
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
PI3Kα is a key lipid kinase in the PI3K/Akt pathway. Its frequent oncogenic mutations make it a primary drug target. Calmodulin (CaM) activates PI3Kα independently of extracellular signals, indicating a significant role in oncogenic PI3Kα activation. Here, we reveal the atomic-scale structures of CaM in complexes with the nSH2 and cSH2 domains of the regulatory p85α subunit of PI3Kα, and illustrate how CaM activates PI3Kα by targeting the "soft 1-5-10" CaM-binding motifs in both nSH2 and cSH2 domains. Experiment observed CaM binding cSH2 first, followed by nSH2 binding hours later. CaM typically prefers binding helical peptides. Here we observe that, unlike in cSH2, the CaM-binding motif in nSH2 populates a mixed β-sheet/α-helix/random coil structure. The population shift from a β-sheet toward CaM's favored α-helical conformation explains why the nSH2 domain needs a longer time for CaM binding in the experiments. The "soft" CaM-binding motifs in both nSH2 and cSH2 domains establish strong CaM-PI3Kα interactions, collectively facilitating PI3Kα activation. This work uncovers the structural basis for CaM-driven PI3Kα activation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.