SEX HORMONE-BINDING GLOBULIN ANDROGEN-BINDING PROTEIN - STEROID-BINDING AND DIMERIZATION DOMAINS

Plasma sex hormone-binding globulin (SHBG) and testicular androgen-bin ding protein (ABP) are homodimeric glycoproteins that share the same p rimary structure, and differ only with respect to the types of oligosa ccharides associated with them. The biological significance of these d ifferences is not understood, but enzymatically deglycosylated SHBG an d a non-glycosylated SHBG mutant both bind steroids normally. Various affinity-labelling experiments, and studies of recombinant SHBG mutant s have indicated that a region encompassing and including Met-139 in h uman SHBG represents an important component of its steroid-binding sit e. Analyses of chimeric proteins comprising various portions of human SHBG and rat ABP have also indicated that residues important for the m uch higher affinity of human SHBG for steroid ligands are probably loc ated within the N-terminal portion of these molecules. Recent studies of SHBG mutants have confirmed this, and a deletion mutant containing only the first 205 N-terminal residues of human SHBG has been produced which dimerizes and binds steroids appropriately. The introduction of amino-acid substitutions between Lys-134 and Phe-148 of SHBG has also indicated that residues including and immediately N-terminal of Met-1 39 may influence steroid-binding specificity, while those immediately C-terminal of Met-139 represent at least a part of the dimerization do main. These studies have also demonstrated that dimerization is induce d by the presence of steroid ligand in the binding site, and that diva lent cations play an important role in this process. Together, these d ata have led us to conclude that SHBG is a modular protein, which comp rises an N-terminal steroid-binding and dimerization domain, and a C-t erminal domain containing a highly-conserved consensus sequence for gl ycosylation that may be required for other biological activities, such as cell-surface recognition.