Structural model of human alpha(1)-microglobulin: proposed scheme for the interaction with the Gla domain of anticoagulant protein C

alpha(1)-Microglobulin (alpha(1)m) is a small glycoprotein with immunomodul atory properties. It is a member of the lipocalin family, a group of protei ns that exhibit a well-conserved three-dimensional structure despite low se quence identity and that are known to bind small hydrophobic ligands. The t ypes of ligands carried by alpha(1)m are still unknown, but it is known tha t this protein has yellow-brown chromophores attached to three lysines at p osition 92, 118 and 130. alpha(1)m has one unpaired cysteine residue (Cys 3 4) that can form a disulphide bond with other proteins that also possess an exposed free unpaired cysteine. For instance, alpha(1)m interacts with the protein C (PC) Gla domain containing the Arg(9)Cys or Ser12Cys substitutio n. In order to gain insights about the alpha(1)m molecule and analyze the i ntriguing alpha(1)m-Gla domain interaction, it was decided to use bioinform atics. The three-dimensional structures of alpha(1)m and PC Gla domain were predicted, alpha(1)m Cys 34 is solvent exposed and located near the entran ce of the ligand-binding pocket. The chromophore-carrying lysines are found buried into the pocket, and the area around the entrance of this cavity di splays about 10 positively charged residues. This electropositive region in alpha(1)m complements the essentially electronegative Gla domain and may p lay a role during intermolecular interactions. In addition, a few hydrophob ic residues surround alpha(1)m Cys 34 and could be of importance during its interaction with macromolecular ligands. Blood Coagul Fibrinolysis 11:261- 275 (C) 2000 Lippincott Williams & Wilkins.