Identification of a binding site in protease nexin I ( PN1) required for the receptor mediated internalization of PN1-thrombin complexes.
An overlapping synthetic peptide library was constructed representing most of the mature protease nexin I ( PN1) sequence from the amino terminus to the reactive center. This library, along with peptides from the heparin binding domain and from the region carboxyl-terminal to the P1 residue of the cleavage site, was screened for the inhibition of 125I-thrombin (Th)-PN1 complex binding and degradation. A peptide corresponding to residues Pro47-Ile58 in the PN1 sequence was identified as a potent inhibitor of 125I-Th- PN1 complex degradation, although it did not affect binding significantly. Pro47-Ile58 was shown to competitively inhibit the low density lipoprotein receptor-related protein (LRP)/alpha2-macroglobulin receptor- mediated endocytosis of 125I-Th- PN1 complexes in mouse embryo fibroblasts. Pro47-Ile58 is an apparent transition sequence in PN1, separating sheet-6B and helix-B. The sequence of Pro47-Ile58, PHDNIVISPHGI, suggests that it forms a loop structure defined by the seven underlined amino acids bordered by proline residues at each end. These studies are the first to identify a putative binding site in a serine protease inhibitor that is required for LRP-mediated internalization.[1]References
- Identification of a binding site in protease nexin I (PN1) required for the receptor mediated internalization of PN1-thrombin complexes. Knauer, M.F., Hawley, S.B., Knauer, D.J. J. Biol. Chem. (1997) [Pubmed]
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