Inhibition of the proteolytic activity of pregnancy-associated plasma protein-A by targeting substrate exosite binding

The Journal of Biological Chemistry
Jakob H MikkelsenC Oxvig

Abstract

The metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) cleaves both insulin-like growth factor (IGF)-binding protein 4 (IGFBP-4) and -5 at a single site in their central domain causing the release of bioactive IGF. Inhibition of IGF signaling is relevant in human disease, and several drugs in development target the IGF receptor. However, inhibition of PAPP-A activity may be a valuable alternative. We have generated monoclonal phage-derived single chain fragment variable (scFv) antibodies which selectively inhibit the cleavage of IGFBP-4 by PAPP-A, relevant under conditions where cleavage of IGFBP-4 represents the final step in the delivery of IGF to the IGF receptor. None of the antibodies inhibited the homologous proteinase PAPP-A2, which allowed mapping of antibody binding by means of chimeras between PAPP-A and PAPP-A2 to the C-terminal Lin12-Notch repeat module, separated from the proteolytic domain by almost 1000 amino acids. Hence, the antibodies define a substrate binding exosite that can be targeted for the selective inhibition of PAPP-A proteolytic activity against IGFBP-4. In addition, we show that the Lin12-Notch repeat module reversibly binds a calcium ion and that bound calcium is required for antibod...Continue Reading

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Citations

Aug 18, 2009·The Journal of Biological Chemistry·Ikuo HayashiTakeshi Iwatsubo
Dec 18, 2013·Journal of Immunological Methods·Jakob H MikkelsenClaus Oxvig
Jan 27, 2009·Toxicon : Official Journal of the International Society on Toxinology·Melissa Pires-AlvesBrenda A Wilson
Dec 18, 2009·Journal of Molecular Recognition : JMR·Rebecca L Rich, David G Myszka
Nov 23, 2013·Expert Opinion on Therapeutic Targets·Rikke HjortebjergJan Frystyk
Jan 27, 2015·Journal of Cell Communication and Signaling·Claus Oxvig
Sep 4, 2013·Current Opinion in Structural Biology·Weiru WangRobert A Lazarus
Mar 1, 2018·British Journal of Pharmacology·Salvatore Santamaria, Rens de Groot
Dec 31, 2016·Aging Cell·Cheryl A Conover, Claus Oxvig
May 31, 2018·Journal of Molecular Endocrinology·Cheryl A Conover, Claus Oxvig
Sep 23, 2014·Journal of Cell Science·Kasper Kjaer-SorensenClaus Oxvig

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