Dataset Information

Calmodulin (CaM) Activates PI3K? by Targeting the "Soft" CaM-Binding Motifs in Both the nSH2 and cSH2 Domains of p85?.

ABSTRACT: PI3K? is a key lipid kinase in the PI3K/Akt pathway. Its frequent oncogenic mutations make it a primary drug target. Calmodulin (CaM) activates PI3K? independently of extracellular signals, indicating a significant role in oncogenic PI3K? activation. Here, we reveal the atomic-scale structures of CaM in complexes with the nSH2 and cSH2 domains of the regulatory p85? subunit of PI3K?, and illustrate how CaM activates PI3K? 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 ?-sheet/?-helix/random coil structure. The population shift from a ?-sheet toward CaM's favored ?-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-PI3K? interactions, collectively facilitating PI3K? activation. This work uncovers the structural basis for CaM-driven PI3K? activation.

SUBMITTER: Zhang M

PROVIDER: S-EPMC6422767 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Calmodulin (CaM) Activates PI3Kα by Targeting the "Soft" CaM-Binding Motifs in Both the nSH2 and cSH2 Domains of p85α.

Zhang Mingzhen M Li Zhigang Z Wang Guanqiao G Jang Hyunbum H Sacks David B DB Zhang Jian J Gaponenko Vadim V Nussinov Ruth R

The journal of physical chemistry. B 20180808 49

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 do ...[more]

PMID: 30047727

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Project description:BackgroundCommon phylogenomic approaches for recovering phylogenies are often time-consuming and require annotations for orthologous gene relationships that are not always available. In contrast, alignment-free phylogenomic approaches typically use structure and oligomer frequencies to calculate pairwise distances between species. We have developed an approach to quickly calculate distances between species based on codon aversion.MethodsUtilizing a novel alignment-free character state, we present CAM, an alignment-free approach to recover phylogenies by comparing differences in codon aversion motifs (i.e., the set of unused codons within each gene) across all genes within a species. Synonymous codon usage is non-random and differs between organisms, between genes, and even within a single gene, and many genes do not use all possible codons. We report a comprehensive analysis of codon aversion within 229,742,339 genes from 23,428 species across all kingdoms of life, and we provide an alignment-free framework for its use in a phylogenetic construct. For each species, we first construct a set of codon aversion motifs spanning all genes within that species. We define the pairwise distance between two species, A and B, as one minus the number of shared codon aversion motifs divided by the total codon aversion motifs of the species, A or B, containing the fewest motifs. This approach allows us to calculate pairwise distances even when substantial differences in the number of genes or a high rate of divergence between species exists. Finally, we use neighbor-joining to recover phylogenies.ResultsUsing the Open Tree of Life and NCBI Taxonomy Database as expected phylogenies, our approach compares well, recovering phylogenies that largely match expected trees and are comparable to trees recovered using maximum likelihood and other alignment-free approaches. Our technique is much faster than maximum likelihood and similar in accuracy to other alignment-free approaches. Therefore, we propose that codon aversion be considered a phylogenetically conserved character that may be used in future phylogenomic studies.AvailabilityCAM, documentation, and test files are freely available on GitHub at https://github.com/ridgelab/cam.

Dataset Information

Calmodulin (CaM) Activates PI3K? by Targeting the "Soft" CaM-Binding Motifs in Both the nSH2 and cSH2 Domains of p85?.

Publications

Calmodulin (CaM) Activates PI3Kα by Targeting the "Soft" CaM-Binding Motifs in Both the nSH2 and cSH2 Domains of p85α.

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