| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 278, Issue 4, 2106-2117, January 24, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Department of Molecular Biology, Science Park, University
of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark
Pregnancy-associated plasma protein-A
(PAPP-A) is a metzincin superfamily metalloproteinase responsible for
cleavage of insulin-like growth factor-binding protein-4, thus causing
release of bound insulin-like growth factor. PAPP-A is secreted as a
dimer of 400 kDa but circulates in pregnancy as a disulfide-bound
500-kDa 2:2 complex with the proform of eosinophil major basic protein
(pro-MBP), recently shown to function as a proteinase inhibitor of
PAPP-A. Except for PAPP-A2, PAPP-A does not share global similarity
with other proteins. Three lin-notch (LNR or LIN-12) modules and five complement control protein modules (also known as SCR modules) have
been identified in PAPP-A by sequence similarity with other proteins,
but no data are available that allow unambiguous prediction of
disulfide bonds of these modules. To establish the connectivities of
cysteine residues of the PAPP-A·pro-MBP complex, biochemical analyses
of peptides derived from purified protein were performed. The PAPP-A
subunit contains a total of 82 cysteine residues, of which 81 have been
accounted for. The pro-MBP subunit contains 12 cysteine residues, of
which 10 have been accounted for. Within the 2:2 complex, PAPP-A is
dimerized by a single disulfide bond; pro-MBP is dimerized by two
disulfides, and each PAPP-A subunit is connected to a pro-MBP subunit
by two disulfide bonds. All other disulfides are intrachain bridges. We
also show that of 13 potential sites for N-linked
carbohydrate substitution of the PAPP-A subunit, 11 are occupied. The
large number of disulfide bonds of the PAPP-A·pro-MBP complex imposes
many restraints on polypeptide folding, and knowledge of the disulfide
pattern of PAPP-A will facilitate structural studies based on
recombinant expression of individual, putative PAPP-A domains.
Furthermore, it will allow rational experimental design of functional
studies aimed at understanding the formation of the PAPP-A·pro-MBP
complex, as well as the inhibitory mechanism of pro-MBP.
Complex of Pregnancy-associated Plasma Protein-A and the Proform
of Eosinophil Major Basic Protein
DISULFIDE STRUCTURE AND CARBOHYDRATE ATTACHMENT SITES*
,
*
This work was supported by grants from the Novo Nordic
Foundation, the Danish Natural Science Research Council, and Danish Medical Research Council.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Institute of Biochemistry and Molecular Biology,
University of Wroclaw, 50-137 Wroclaw, Poland.
§
To whom correspondence should be addressed. E-mail:
co@mb.au.dk.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Gyrup, M. Christiansen, and C. Oxvig Quantification of Proteolytically Active Pregnancy-Associated Plasma Protein-A with an Assay Based on Quenched Fluorescence Clin. Chem., May 1, 2007; 53(5): 947 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Weyer, H. B. Boldt, C. B. Poulsen, K. Kjaer-Sorensen, C. Gyrup, and C. Oxvig A Substrate Specificity-determining Unit of Three Lin12-Notch Repeat Modules Is Formed in Trans within the Pappalysin-1 Dimer and Requires a Sequence Stretch C-terminal to the Third Module J. Biol. Chem., April 13, 2007; 282(15): 10988 - 10999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Glerup, S. Kloverpris, L. S. Laursen, F. Dagnaes-Hansen, S. Thiel, C. A. Conover, and C. Oxvig Cell Surface Detachment of Pregnancy-associated Plasma Protein-A Requires the Formation of Intermolecular Proteinase-Inhibitor Disulfide Bonds and Glycosaminoglycan Covalently Bound to the Inhibitor J. Biol. Chem., January 19, 2007; 282(3): 1769 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tallant, R. Garcia-Castellanos, J. Seco, U. Baumann, and F. X. Gomis-Ruth Molecular Analysis of Ulilysin, the Structural Prototype of a New Family of Metzincin Metalloproteases J. Biol. Chem., June 30, 2006; 281(26): 17920 - 17928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q.-P. Qin, S. Kokkala, J. Lund, N. Tamm, X. Qin, M. Lepantalo, and K. Pettersson Immunoassays Developed for Pregnancy-Associated Plasma Protein-A (PAPP-A) in Pregnancy May Not Recognize PAPP-A in Acute Coronary Syndromes Clin. Chem., March 1, 2006; 52(3): 398 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Glerup, H. B. Boldt, M. T. Overgaard, L. Sottrup-Jensen, L. C. Giudice, and C. Oxvig Proteinase Inhibition by Proform of Eosinophil Major Basic Protein (pro-MBP) Is a Multistep Process of Intra- and Intermolecular Disulfide Rearrangements J. Biol. Chem., March 18, 2005; 280(11): 9823 - 9832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. B. Boldt, K. Kjaer-Sorensen, M. T. Overgaard, K. Weyer, C. B. Poulsen, L. Sottrup-Jensen, C. A. Conover, L. C. Giudice, and C. Oxvig The Lin12-Notch Repeats of Pregnancy-associated Plasma Protein-A Bind Calcium and Determine Its Proteolytic Specificity J. Biol. Chem., September 10, 2004; 279(37): 38525 - 38531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Conover, L. K. Bale, M. T. Overgaard, E. W. Johnstone, U. H. Laursen, E.-M. Fuchtbauer, C. Oxvig, and J. van Deursen Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development Development, March 1, 2004; 131(5): 1187 - 1194. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
