Horm Metab Res 1999; 31(2/03): 216-225
DOI: 10.1055/s-2007-978722
© Georg Thieme Verlag Stuttgart · New York

The Heparin Binding Domain of Insulin-Like Growth Factor Binding Protein (IGFBP)-3 Increases Susceptibility of IGFBP-3 to Proteolysis

Susan K. Durham1 , A. Suwanichkul1 , J. D. Hayes2 , A. C. Herington3 , D. R. Powell1 , P. G. Campbell2
  • 1Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
  • 2Orthopaedic Research Laboratory, Allegheny University of Health Sciences, Pittsburgh, PA, USA
  • 3School of Life Sciences, Queensland University of Technology, Brisbane, Australia
Further Information

Publication History

1998

1998

Publication Date:
19 April 2007 (online)

IGFBP-3 proteolysis clears IGFBP-3 from body fluids and increases IGF bioavailability. As shown here, native human IGFBP-3 was cleaved by proteases in media conditioned by hamster and insect cells. This proteolysis was less pronounced for IGFBP-3 containing a mutated heparin binding domain, and was prevented by purifying IGFBP-3 on an IGF-I affinity column in the presence of 2M sodium chloride, suggesting that the responsible protease(s) binds the IGFBP-3 heparin binding domain. To determine if any human proteases act this way, we first studied plasma prekallikrein since it can copurify with IGFBP-3, and found: 1) [125]IGFBP-3 binds to prekallikrein immobilized either on nitrocellulose or on immunocapture plates; 2) the IGFBP-3 heparin binding domain participates in forming the IGFBP-3/prekallikrein complex; 3) the binary IGFBP-3/prekallikrein complex can bind IGF-I to form a ternary complex; and 4) activation of prekallikrein to α-kallikrein by Factor XIIa resulted in proteolysis of bound IGFBP-3. This work suggests: 1) cleavage of IGFBP-3 by a protease may be aided by the ability of the protease zymogen to directly bind the IGFBP-3 heparin binding domain; and 2) direct binding of protease zymogens to IGFBP-3 may explain some instances where IGFBP-3 is preferentially proteolyzed in the presence of other IGFBPs.

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