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

Guanqiao Wang1, Mingzhen Zhang2, Hyunbum Jang2

  • 1Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education , Shanghai Jiao-Tong University School of Medicine , Shanghai 200025 , China.

Biochemistry
|March 2, 2018
PubMed

Insights

Calmodulin (CaM) binding to PI3Kα’s p85α subunit activates the kinase in cancer by relieving autoinhibition. This interaction, detailed by NMR, reveals CaM’s role in promoting cell proliferation and survival.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Biology

Background:

  • Calmodulin (CaM) is a calcium sensor protein.
  • PI3Kα is a dual-specificity kinase involved in cell signaling.
  • CaM interaction with PI3Kα's p85α subunit activates PI3Kα in adenocarcinomas, promoting cancer progression.

Purpose of the Study:

  • To elucidate the structural basis of CaM interaction with the p85α regulatory subunit of PI3Kα.
  • To understand how CaM binding leads to PI3Kα activation.
  • To explore the broader implications of CaM-mediated kinase activation.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy to determine structural details.
  • Biochemical assays to study protein interactions and kinase activity.
  • Amino acid sequence analysis to identify conserved motifs.

Main Results:

  • The cSH2 domain of p85α binds CaM via two CaM-binding motifs, interacting with both lobes and the linker of CaM.
  • CaM binding causes the cSH2 domain to expose a tryptophan residue.
  • Multiple binding modes are possible due to the flexibility of CaM and cSH2.
  • CaM binding releases the autoinhibition of the p110 catalytic subunit of PI3Kα.

Conclusions:

  • CaM directly binds to the cSH2 domain of p85α, structurally activating PI3Kα.
  • This activation mechanism, involving CaM relieving kinase autoinhibition, is crucial for cancer cell proliferation, survival, and migration.
  • CaM-binding motifs are prevalent in non-RTK SH2 domains, suggesting a conserved activation mechanism for other kinases.

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