Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance

Nat Commun. 2016 Mar 18;7:11030. doi: 10.1038/ncomms11030.

Abstract

Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown. Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules. The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization. Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem. Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells. This study demonstrates protein dimerization via haem-haem stacking, which has not been seen in eukaryotes, and provides insights into its functional significance in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon Monoxide / metabolism
  • Cell Proliferation
  • Crystallography, X-Ray
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / metabolism
  • Heme / metabolism*
  • Humans
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Protein Binding
  • Protein Multimerization*
  • Receptors, Progesterone / metabolism*
  • Receptors, sigma / metabolism*
  • Signal Transduction / drug effects
  • Solutions

Substances

  • Membrane Proteins
  • PGRMC1 protein, human
  • Receptors, Progesterone
  • Receptors, sigma
  • Solutions
  • sigma-2 receptor
  • Heme
  • Carbon Monoxide
  • Cytochrome P-450 Enzyme System
  • ErbB Receptors