Pregnancy-associated Plasma Protein-A2 (PAPP-A2), a Novel Insulin-like Growth Factor-binding Protein-5 Proteinase

Overgaard, Michael Toft; Boldt, Henning B.; Laursen, Lisbeth S.; Sottrup‐Jensen, Lars; Conover, Cheryl A.; Oxvig, Claus

doi:10.1074/jbc.m102191200

Cited by 229 publications

(243 citation statements)

References 30 publications

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“…These studies suggested lower efficiency in vitro of PAPP-A and PAPP-A2 against IGFBP-4 and -5 than ulilysin when using similar detection techniques (Tallant et al, 2006). For the human enzymes, standard assay conditions entailed a protease/ substrate ratio of approximately 1:10 or 1:20 and incubation times of up to 20 h Overgaard et al, 2001). In contrast, ulilysin produced comparable cleavage levels (as inferred from SDS-PAGE) in our hands at a weight ratio of 1:300 and reaction times of 2-4 h. However, more recent detailed kinetic studies following a different analytical approach revealed that PAPP-A cleaved IGFBP-4 and -5 in a much more efficient manner than ulilysin and that the hydrolysis of IGFBP-4 was dependent on IGF binding for both proteases (Gyrup and Oxvig, 2007).…”

Section: Proteolytic Assays Of Protein Substrates and Fluorigenic Pepmentioning

confidence: 99%

“…For this protein, which is also found in mammals, specific IGF-independent cleavage of IGFBP-5 identical to PAPP-A and partial activity against IGFBP-3 have been reported (Farr et al, 2000;Bayes-Genis et al, 2001b;Overgaard et al, 2001). These pappalysins contain the sequence motif His-GluXxx-Xxx-His-Xxx-Xxx-Gly-Xxx-Xxx-His/Asp (Xxx for any residue), a zinc-binding consensus sequence (ZBCS) that is the hallmark of the metzincin clan of MPs.…”

Section: Introductionmentioning

confidence: 99%

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Activity of ulilysin, an archaeal PAPP-A-related gelatinase and IGFBP protease

Tallant

García‐Castellanos

Marrero

et al. 2007

BCHM

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Human growth and development are conditioned by insulin-like growth factors (IGFs), which have also implications in pathology. Most IGF molecules are sequestered by IGF-binding proteins (IGFBPs) so that exertion of IGF activity requires disturbance of these complexes. This is achieved by proteolysis mediated by IGFBP proteases, among which the best characterised is human PAPP-A, the first member of the pappalysin family of metzincins. We have previously identified and studied the only archaeal homologue found to date, Methanosarcina acetivorans ulilysin. This is a proteolytically functional enzyme encompassing a pappalysin catalytic domain and a pro-domain involved in maintenance of latency of the zymogen, proulilysin. Once activated, the protein hydrolyses IGFBP-2 to -6 and insulin chain b in vitro. We report here that ulilysin is also active against several other substrates, viz (azo)casein, azoalbumin, and extracellular matrix components. Ulilysin has gelatinolytic but not collagenolytic activity. Moreover, the proteolysis-resistant skeletal proteins actin and elastin are also cleaved, as is fibrinogen, but not plasmin and a1-antitrypsin from the blood coagulation cascade. Ulilysin develops optimal activity at pH 7.5 and strictly requires peptide bonds preceding an arginine residue, as determined by means of a novel fluorescence resonance energy transfer assay, thus pointing to biotechnological applications as an enzyme complementary to trypsin.These two authors contributed equally to this work. a

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Section: Proteolytic Assays Of Protein Substrates and Fluorigenic Pepmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activity of ulilysin, an archaeal PAPP-A-related gelatinase and IGFBP protease

Tallant

García‐Castellanos

Marrero

et al. 2007

BCHM

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“…PAPP-A is the founding member of the pappalysin family (12,13) within the metzincin superfamily of metalloproteinases (14,15), also including its only known homologue, PAPP-A2, which cleaves IGFBP-5, but not IGFBP-4 (16). The 1558 3 -residue PAPP-A2 shares 46% of its residues with the 1547-residue PAPP-A (17), and they display the same domain organization with a laminin G-like domain and a proteolytic domain in the N-terminal part (18), a central region of ϳ500 residues with unknown domain composition, and a C-terminal part with five complement control protein (CCP) modules that mediate cell surface adhesion of PAPP-A (19,20).…”

mentioning

confidence: 99%

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

Weyer

Boldt

Poulsen

et al. 2007

Journal of Biological Chemistry

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Members of the pappalysin family of metzincin metalloproteinases, pregnancy-associated plasma protein-A (PAPP-A, pappalysin-1) and PAPP-A2 (pappalysin-2), regulate the bioavailability of insulin-like growth factors (IGFs) by specific proteolytic inactivation of IGF-binding proteins (IGFBPs). PAPP-A cleaves IGFBP-4 and IGFBP-5, whereas PAPP-A2 cleaves only IGFBP-5. The pappalysins contain three Lin12-Notch repeat (LNR1-3) modules, previously considered unique to the Notch receptor family in which they function to regulate receptor cleavage. In contrast to the Notch receptor where three LNR modules are tandemly arranged, LNR3 is separated by more than 1000 residues from LNR1-2 in the pappalysin sequence. Each of the three LNR modules of PAPP-A is required for proteolysis of IGFBP-4, but not IGFBP-5. However, we here find that a C-terminal truncated variant of PAPP-A, which lacks LNR3 and therefore activity against IGFBP-4, cleaves IGFBP-4 when co-expressed with a PAPP-A variant, which is mutated in the active site. This suggests that LNR3 from the inactive subunit interacts in trans with LNR1-2 of the truncated PAPP-A subunit to form a functional trimeric LNR unit. We also show that formation of such a functional LNR unit depends on dimerization, as dissociation of a mutated non-covalent PAPP-A dimer results in reduced activity against IGFBP-4, but not IGFBP-5. Using PAPP-A/PAPP-A2 chimeras, we demonstrate that PAPP-A2 LNR1-2, but not LNR3, are functionally conserved with respect to IGFBP proteolysis. Additionally, we find that a sequence stretch C-terminal to LNR3 and single residues (Asp 1521 , Arg 1529 , and Asp 1530 ) within this are required for LNR functionality.The metalloproteinase pregnancy-associated plasma protein-A (PAPP-A, pappalysin-1, EC 3.4.24.79) 2 is secreted as a disulfide-linked 400-kDa homodimer (1) that cleaves insulinlike growth factor binding proteins (IGFBP)-4 (2) and IGFBP-5 (3). Through this proteolytic activity, PAPP-A causes the release of active IGF and thereby regulates its bioavailability in several biological systems. In particular, the role of PAPP-A has been studied in ovarian follicular development (4), implantation (5), fetal development (6 -8), wound healing (9), and atherosclerosis (10, 11). PAPP-A is the founding member of the pappalysin family (12, 13) within the metzincin superfamily of metalloproteinases (14, 15), also including its only known homologue, PAPP-A2, which cleaves IGFBP-5, but not IGFBP-4 (16). The 1558 3 -residue PAPP-A2 shares 46% of its residues with the 1547-residue PAPP-A (17), and they display the same domain organization with a laminin G-like domain and a proteolytic domain in the N-terminal part (18), a central region of ϳ500 residues with unknown domain composition, and a C-terminal part with five complement control protein (CCP) modules that mediate cell surface adhesion of 20). The pappalysins also contain three Lin12-Notch repeat (LNR) modules, previously considered unique to the Notch receptor family. But in contrast to the Notch receptors, which...

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“…This indicates that the IGF-IGFBP-4 complex would persist when exposed to the low pH of both the early and late endosomes within cells (Clague 1998), whereas IGFBP-5 affinity drops drastically with lower pH and thus the IGF-IGFBP-5 complex would tend to dissociate in early and late endosomes. The preservation of the IGF-IGFBP-4 complex over a wide yet physiological pH range may also ensure inactivation of IGFBP-4 by IGF-dependent proteases (Claussen et al 1997, RemacleBonnet et al 1997, Byun et al 2001, Overgaard et al 2001. At pH 7·4, the affinity of L6 cell-derived soluble IGFBP-4 for either IGF-I or IGF-II is three-to fourfold higher than the IGF-1R of the same cells in both the presence and absence of Zn 2+ (Table 2 versus Table 3).…”

Section: I-igf-ii Bindingmentioning

confidence: 99%