Serpins: A Conformational Trap

Fig. 1. Representative crystal structures of members of the serpin family. Cartoon diagrams were produced using MOLSCRIPT (21): A. bovine trypsin proteinase inhibitor, pdb accession 1BPI B. cleaved antitrypsin, 7API C. inact ovalbumin, 1OVA D. inact antitrypsin, 1QLP E. docking complex between inactive trypsin and serpin 1K, 1I99 F. covalent complex between trypsin and antitrypsin, 1EZX G. latent PAI-1 (E.J. Goldsmith) H. antitrypsin polymer, 1D5S I. δ-antichymotrypsin, 1QMN intracellular roles (2). Most serpins identified to date are inhibitory, although their proteinase targets are not restricted to the serine proteinases. In particular, several serpins have been identified that inhibit papain-like cysteine proteinases (e.g. Squamous Cell Carcinoma Antigen1 [SCCA-1]) and the viral serpin crmA is an effective inhibitor of the caspase, ICE-1. In addition to the inhibitory serpins, certain members were identified that had evolved to perform noninhibitory roles, such as hormone delivery (angiotensinogen), the inhibition of metastasis (maspin) and controlling protein folding (47kDa Heat Shock Protein or HSP47). To date, over 500 serpin sequences have been deposited in GENPEPT with serpins found in the higher plants, animals and viruses (3). A phylogenetic investigation of the serpin superfamily reveals that the serpins can be divided into 16 distinct clades (or families). To date no prokaryote or fungal serpin has been identified and the nature of the ancestral serpin remains obscure.