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Method to Visualize and Analyze Membrane Interacting Proteins by Transmission Electron Microscopy
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The membrane-bound enzyme CD38 exists in two opposing orientations.

Yong Juan Zhao1, Connie Mo Ching Lam, Hon Cheung Lee

  • 1Department of Physiology, Li Ka Shing School of Medicine, The University of Hong Kong, Hong Kong, China.

Science Signaling
|September 13, 2012
PubMed
Summary

CD38 enzyme orientation influences intracellular calcium signaling. Researchers found CD38 can flip its catalytic domain, impacting cyclic adenosine 5'-diphosphate-ribose (cADPR) levels and cell signaling.

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Area of Science:

  • Cell biology
  • Biochemistry
  • Molecular signaling

Background:

  • CD38 is a transmembrane enzyme critical for cyclic adenosine 5'-diphosphate-ribose (cADPR) metabolism.
  • cADPR acts as an intracellular calcium (Ca2+) mobilizing messenger.
  • The precise mechanism of CD38's intracellular cADPR metabolism has been debated due to its presumed extracellular catalytic domain.

Purpose of the Study:

  • To investigate the membrane orientation of the CD38 enzyme.
  • To determine how CD38's orientation affects intracellular cADPR levels and Ca2+ signaling.
  • To elucidate the mechanism regulating CD38's signaling activity.

Main Methods:

  • Development of specific antibodies against the amino-terminal segment of CD38.
  • Analysis of CD38 orientation on HL-60 cells during differentiation and on human monocytes/U937 cells upon interferon-γ activation.
  • Site-directed mutagenesis to alter CD38 membrane orientation.
  • Expression of CD38 constructs in transfected cells to assess cADPR concentrations.

Main Results:

  • Two opposing orientations of CD38 (type II and type III) were identified on cell surfaces.
  • Retinoic acid-induced differentiation of HL-60 cells and interferon-γ activation of monocytes/U937 cells showed co-distribution of both CD38 orientations.
  • Mutagenesis of cationic amino acids in the amino-terminal segment converted CD38 orientation to exclusively type III.
  • Expression of type III CD38 increased intracellular cADPR concentrations.

Conclusions:

  • CD38 exists in multiple membrane orientations, including a type III orientation with an intracellular catalytic domain.
  • The flipping of CD38's catalytic domain between extracellular and intracellular locations may regulate its Ca2+ signaling function.
  • Understanding CD38 orientation is crucial for comprehending its role in cellular signaling pathways.