Fig. 1. The major NLS binding motif is conserved in the steroid receptor hinge region. (A) The amino acid sequences from the hinge regions of the androgen receptor (AR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), nucleoplasmin and the SV40 large T antigen were aligned using Multalin (http://bioinfo.genopole-toulouse.prd.fr/multalin/). Conserved basic residues are in bold. The classical bipartite NLS is from nucleoplasmin, and binds to importin- via its minor and major NLS motif, boxed in grey. SV40 is a classical monopartite NLS and binds to the major NLS-binding pockets of importin- (area shaded grey). The sequence alignment of several nuclear hormone receptors reveals significant homology with these classical NLSs, with conserved basic residues in bold. (B) Scheme of the human AR, showing the N-terminal transactivation domain (TAD), DNA-binding domain (DBD), hinge domain (H) and ligand-binding domain (LBD). (C) The second zinc finger of the DBD and the hinge region. The ordered terminal -helix of the DBD is boxed, and the unstructured hinge region is underlined. The conserved NLS motif is in bold. Only the stretch of positively charged residues (629RKLKK633; bold) lies within the unstructured hinge domain, whereas the charged residues of the C-terminal lie within the DBD -helix. Adapted from Shaffer et al. (Shaffer et al., 2004). (D) Pathological substitutional mutations within this region that lead to AIS or prostate cancer (CaP).