Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release

J Biol Chem. 2007 Oct 5;282(40):29594-603. doi: 10.1074/jbc.M705014200. Epub 2007 Jul 19.

Abstract

Corticosteroid-binding globulin (CBG) is a serine proteinase inhibitor (serpin) family member that transports glucocorticoids in blood and regulates their access to target cells. The 1.9A crystal structure of rat CBG shows that its steroid-binding site resembles the thyroxin-binding site in the related serpin, thyroxin-binding globulin, and mutagenesis studies have confirmed the contributions of key residues that constitute the steroid-binding pocket. Unlike thyroxin-bound thyroxin-binding globulin, the cortisol-bound CBG displays an "active" serpin conformation with the proteinase-sensitive, reactive center loop (RCL) fully expelled from the regulatory beta-sheet A. Moreover, the CBG structure allows us to predict that complete insertion of the proteolytically cleaved RCL into the serpin fold occurs in concert with a displacement and unwinding of helix D that would disrupt the steroid-binding site. This allosteric coupling between RCL positioning and occupancy of the CBG steroid-binding site, which resembles the ligand (glycosamino-glycan)-dependent activation of the thrombin inhibitory serpins heparin cofactor II and anti-thrombin RCLs, ensures both optimal recognition of CBG by target proteinases and efficient release of steroid to sites of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Transport
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray / methods
  • Humans
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Rats
  • Sequence Homology, Amino Acid
  • Steroids / chemistry
  • Steroids / metabolism*
  • Swine
  • Transcortin / chemistry
  • Transcortin / physiology*

Substances

  • Steroids
  • Transcortin

Associated data

  • PDB/2V6D