IGF dependent modulation of IGF binding protein (IGFBP) proteolysis by pregnancy-associated plasma protein-A (PAPP-A): multiple PAPP-A-IGFBP interaction sites.
Biochim Biophys Acta
; 1830(3): 2701-9, 2013 Mar.
Article
in En
| MEDLINE
| ID: mdl-23671931
ABSTRACT
BACKGROUND:
Pregnancy-associated plasma protein-A (PAPP-A) is a local regulator of insulin-like growth factor (IGF) bioavailability in physiological systems, but many structural and functional aspects of the metzincin metalloproteinase remain to be elucidated. PAPP-A cleaves IGF binding protein (IGFBP)-4 and IGFBP-5. Cleavage of IGFBP-4, but not IGFBP-5, depends on the binding of IGF before proteolysis by PAPP-A can occur. The paralogue PAPP-A2 has two substrates among the six IGFBPs IGFBP-3 and IGFBP-5.METHODS:
Sets of chimeric proteins between IGFBP-4 and -5, and IGFBP-3 and -5 were constructed to investigate the structural requirements for IGF modulation. At the proteinase level, we investigated the importance of individual acidic amino acids positioned in the proteolytic domain of PAPP-A for proteolytic activity against IGFBP-4 and -5. Interaction between PAPP-A and its substrates was analyzed by surface plasmon resonance. RESULTS ANDCONCLUSION:
We provide data suggesting that the C-terminal domain of the IGFBPs is responsible for IGF-dependent modulation of access to the scissile bond. Loss or reduction of IGFBP proteolysis by PAPP-A was observed upon mutation of residues positioned in the unique 63-residue stretch separating the zinc and Met-turn motifs, and in the short sequence following the Met-turn methionine. A model of the proteolytic domain of PAPP-A suggests the presence of structural calcium ions in the C-terminal subdomain, implicated in IGFBP substrate interactions. GENERALSIGNIFICANCE:
Detailed knowledge of interactions between PAPP-A and its substrates is required to understand the modulatory role of PAPP-A on IGF receptor stimulation.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pregnancy-Associated Plasma Protein-A
/
Somatomedins
/
Insulin-Like Growth Factor Binding Protein 5
/
Insulin-Like Growth Factor Binding Protein 3
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Female
/
Humans
/
Pregnancy
Language:
En
Journal:
Biochim Biophys Acta
Year:
2013
Document type:
Article
Affiliation country:
Denmark