Prolylcarboxypeptidase independently activates plasma prekallikrein (Fletcher factor)

J. Wang, A. Matafonov, H. Madkhali, F. Mahdi, D. Watson, A. H. Schmaier, D. Gailani, Z. Shariat-Madar

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10 Citations (Scopus)

Abstract

Prolylcarboxypeptidase isoform 1 (PRCP1) is capable of regulating numerous autocrines and hormones, such as angiotensin II, angiotensin III, αMSH1-13, and DesArg9 bradykinin. It does so by cleaving a C-terminal PRO-X bond. Recent work also indicates that the human PRCP1 activates plasma prekallikrein (PK) to kallikrein on endothelial cells through an uncharacterized mechanism. This study aims to identify PRCP1 binding interaction and cleavage site on PK. Recently, a cDNA encoding a novel splice variant of the human PRCP1 was identified. This isoform differed only in the N-terminal region of the deduced amino acid sequence. Using structural and functional studies, a combination of peptide mapping and site-directed mutagenesis approaches were employed to investigate the interaction of PRCP1 with PK. Three PRCP peptides, in decreasing order of potency, from 1) the N-terminus of the secreted protein, 2) spanning the opening of the active site pocket, and 3) in the dimerization region inhibit PRCP activation of PK on endothelial cells. Investigations also tested the hypothesis that PRCP cleavage site on PK is between its C-terminal Pro 637 (P637) and Ala 638 (A638). Recombinant forms of PK with C-terminal alanine mutagenesis or a stop codon is activated equally as wild type PK by PRCP. In conclusion, PRCP1 interacts with PK at multiple sites for PK activation. PRCP1 also enhances FXIIa activation of PK, suggesting that its activation site on PK is not identical to that of FXIIa.

Original languageEnglish
Pages (from-to)1173-1185
Number of pages13
JournalCurrent Molecular Medicine
Volume14
Issue number9
Publication statusPublished - 1 Jan 2014
Externally publishedYes

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Keywords

  • Diabetes
  • Hormones
  • Inflammation
  • Kallikrein
  • Obesity
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Molecular Medicine

Cite this

Wang, J., Matafonov, A., Madkhali, H., Mahdi, F., Watson, D., Schmaier, A. H., ... Shariat-Madar, Z. (2014). Prolylcarboxypeptidase independently activates plasma prekallikrein (Fletcher factor). Current Molecular Medicine, 14(9), 1173-1185.