Interaction of Calmodulin with the cSH2 Domain of the p85 Regulatory Subunit

Guanqiao Wang, Mingzhen Zhang, Hyunbum Jang, Shaoyong Lu, Shizhou Lin, Guoqiang Chen, Ruth Nussinov*, Jian Zhang, Vadim Gaponenko

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Calmodulin (CaM) is a calcium sensor protein that directly interacts with the dual-specificity (lipid and protein) kinase PI3Kα through the SH2 domains of the p85 regulatory subunit. In adenocarcinomas, the CaM interaction removes the autoinhibition of the p110 catalytic subunit of PI3Kα, leading to activation of PI3Kα and promoting cell proliferation, survival, and migration. Here we demonstrate that the cSH2 domain of p85α engages its two CaM-binding motifs in the interaction with the N- and C-lobes of CaM as well as the flexible central linker, and our nuclear magnetic resonance experiments provide structural details. We show that in response to binding CaM, cSH2 exposes its tryptophan residue at the N-terminal region to the solvent. Because of the flexible nature of both CaM and cSH2, multiple binding modes of the interactions are possible. Binding of CaM to the cSH2 domain can help release the inhibition imposed on the p110 subunit, similar to the binding of the phosphorylated motif of RTK, or phosphorylated CaM (pCaM), to the SH2 domains. Amino acid sequence analysis shows that CaM-binding motifs are common in SH2 domains of non-RTKs. We speculate that CaM can also activate these kinases through similar mechanisms.

Original languageEnglish
Pages (from-to)1917-1928
Number of pages12
JournalBiochemistry
Volume57
Issue number12
DOIs
StatePublished - 27 Mar 2018

Funding

FundersFunder number
National Institutes of HealthHHSN261200800001E
National Cancer InstituteR01 CA188427, ZIABC010440
University of Illinois at Chicago
Frederick National Laboratory for Cancer Research
National Natural Science Foundation of China81473137, 81322046, 21778037
China Scholarship Council
Shanghai Rising-Star Program13QA1402300

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