TAILIEUCHUNG - Báo cáo khoa học: Mapping of the epitope of a monoclonal antibody protecting plasminogen activator inhibitor-1 against inactivating agents

Plasminogen activator inhibitor-1 (PAI-1) belongs to the serpin family of serine proteinase inhibitors. Serpins inhibit their target proteinases by an ester bond being formed between the active site serine of the proteinase and the P1 residue of the reactive centre loop (RCL) of the serpin, fol-lowed by insertion of the RCL intob-sheet A of the serpin. Concomitantly, there are conformational changes in the flexible joint region lateral tob-sheet A. | Eur. J. Biochem. 270 1672-1679 2003 FEBS 2003 doi Mapping of the epitope of a monoclonal antibody protecting plasminogen activator inhibitor-1 against inactivating agents Julie S. Bodker Troels Wind Jan K. Jensen Martin Hansen Katrine E. Pedersen and Peter A. Andreasen Laboratory of Cellular Protein Science Department of Molecular Biology University of Aarhus Denmark Plasminogen activator inhibitor-1 PAI-1 belongs to the serpin family of serine proteinase inhibitors. Serpins inhibit their target proteinases by an ester bond being formed between the active site serine of the proteinase and the P1 residue of the reactive centre loop RCL of the serpin followed by insertion of the RCL into b-sheet A of the serpin. Concomitantly there are conformational changes in the flexible joint region lateral to b-sheet A. We have now by site-directed mutagenesis mapped the epitope for a monoclonal antibody which protects the inhibitory activity of PAI-1 against inactivation by a variety of agents acting on b-sheet A and the flexible joint region. Curiously the epitope is localized in a-helix C and Ihe loop connecting a-helix I and b-strand 5A on the side of PAI-1 opposite to b-sheet A and distantly from the flexible joint region. By a combination of site-directed mutagenesis and antibody protection against an inactivating organochemical ligand we were able to identify a residue involved in conferring the antibody-induced conformational change from the epitope to the rest of the molecule. We have thus provided evidence for communication between secondary structural elements not previously known to interact in serpins. Keywords cancer cardiovascular disease monoclonal antibody protease serpin. The serpins constitute a protein family of which the best characterized members including a1-proteinase inhibitor antithrombin III and plasminogen activator inhibitor-1 PAI-1 are inhibitors of serine proteinases implicated in processes such as blood coagulation

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