Structural Basis of Protein Kinase Cα Regulation by the C-Terminal Tail

Biophys J. 2018 Apr 10;114(7):1590-1603. doi: 10.1016/j.bpj.2017.12.030.

Abstract

Protein kinase C (PKC) isoenzymes are multi-modular proteins activated at the membrane surface to regulate signal transduction processes. When activated by second messengers, PKC undergoes a drastic conformational and spatial transition from the inactive cytosolic state to the activated membrane-bound state. The complete structure of either state of PKC remains elusive. We demonstrate, using NMR spectroscopy, that the isolated Ca2+-sensing membrane-binding C2 domain of the conventional PKCα interacts with a conserved hydrophobic motif of the kinase C-terminal region, and we report a structural model of the complex. Our data suggest that the C-terminal region plays a dual role in regulating the PKC activity: activating, through sensitization of PKC to intracellular Ca2+ oscillations; and auto-inhibitory, through its interaction with a conserved positively charged region of the C2 domain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Mutation
  • Protein Domains
  • Protein Kinase C-alpha / chemistry*
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism*
  • Rats
  • Static Electricity

Substances

  • Protein Kinase C-alpha
  • Calcium