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J Biol Chem, Vol. 274, Issue 1, 275-281, January 1, 1999
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From the We recently identified a synthetic peptide,
Pro47-Ile58, derived from the mature
protease nexin 1 (PN1) sequence, that inhibited the low density
lipoprotein receptor-related protein (LRP)-mediated internalization of
thrombin-PN1 (Th-PN1) complexes. Presently, we have analyzed this
sequence in Th-PN1 complex catabolism using two independent approaches:
1) An antibody was generated against Pro47-Ile58, which inhibited complex
degradation by 70% but had no effect on the binding of the complexes
to cell surface heparins. This places the structural determinant in PN1
mediating complex internalization by the LRP outside of the
heparin-binding site. 2) Site-directed genetic variants of PN1 with a
single Ala substitution at His48, or two Ala substitutions,
one at His48 and another at Asp49, were
expressed in Sf9 insect cells. The catabolic rate of complexes formed between Th and the singly substituted and doubly substituted variants was lowered to 50 and 15%, respectively, when compared with
the catabolic rate of native Th-PN1 complexes. This is the first
analysis of a structural determinant in a serine
protease inhibitor (SERPIN) required for
LRP-mediated internalization and in part may explain the cryptic nature
of this site in the unreacted serine protease inhibitor.
Department of Developmental and Cell
Biology, School of Biological Sciences, University of California,
Irvine, California 92697 and the § Burnham Institute,
La Jolla, California 92037
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