title: Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release.
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.
authors.affiliation: Lehrstuhl für Biotechnik, Department of Biology, Friedrich-Alexander-University Erlangen-Nuremberg, D-91052 Erlangen, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Klieber
authors.forename: Caroline
authors.initials: C
authors.lastname: Underhill
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Hammond
authors.forename: Yves A
authors.initials: YA
authors.lastname: Muller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013256:Steroids / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D014156:Transcortin / Q000737:chemistry / Q000502:physiology*
chemical_list: D013256:Steroids; D014156:Transcortin