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Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy
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Crystal structure of the atypical protein kinase domain of a TRP channel with phosphotransferase activity

H Yamaguchi1, M Matsushita, A C Nairn

  • 1Howard Hughes Medical Institute, New York, NY 10021, USA.

Molecular Cell
|June 8, 2001
PubMed

Insights

A novel calcium-modulating channel protein kinase was discovered. Its unique structure reveals unexpected similarities to known protein kinases, expanding the known signaling protein families.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Signaling

Background:

  • Transient receptor potential (TRP) channels are crucial for regulating intracellular calcium levels in response to external stimuli.
  • Calcium signaling plays a vital role in numerous cellular processes.
  • The diversity of TRP channels and their regulatory mechanisms are areas of active research.

Purpose of the Study:

  • To characterize a novel transient receptor potential channel with intrinsic kinase activity.
  • To elucidate the structural and evolutionary relationship of this channel's catalytic domain to known protein kinases.
  • To understand the functional significance of the kinase domain in channel activity.

Main Methods:

  • X-ray crystallography was employed to determine the three-dimensional structure of the kinase domain.
  • Bioinformatic analyses were performed to compare the kinase domain's sequence and structure with existing protein kinase and enzyme databases.
  • Functional assays were conducted to assess the necessity of the kinase domain for channel function.

Main Results:

  • A novel TRP channel was identified with autophosphorylation and transphosphorylation capabilities on serine and threonine residues.
  • The catalytic domain of this channel kinase exhibits no significant sequence homology to classical eukaryotic protein kinases.
  • Structural analysis revealed unexpected similarities in the catalytic core to eukaryotic protein kinases and to metabolic enzymes possessing ATP-grasp domains.
  • The kinase domain was found to be essential for the channel's overall function.

Conclusions:

  • The discovery of a TRP channel with intrinsic, structurally unique kinase activity expands the known repertoire of calcium-modulating proteins.
  • The structural and evolutionary links identified suggest a broader distribution of the eukaryotic protein kinase superfamily than previously recognized.
  • This finding has significant implications for understanding calcium signaling pathways and the evolution of protein kinases.

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