Macromolecular Substrate Affinity for Free Factor Viia is Independent of a Buried Protease Domain N-terminus.
From: Haemostasis Biochemistry, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark. egpe@novonordisk.com
Biochemical and biophysical research communications
- Publish Date: Mar 2006
- ISSN: 0006-291X
- Volume: 341
- Issue: 1
- Pages: 28-32
- Medium: Print
- Language: English
- Citation (JAMA): Persson Egon, et al. Macromolecular Substrate Affinity for Free Factor Viia is Independent of a Buried Protease Domain N-terminus.. Biochem. Biophys. Res. Commun. Mar 2006;341:28-32
Abstract
The initial recognition and binding of macromolecular substrates by factor VIIa (FVIIa) in complex with tissue factor has been shown to be mediated by areas distinct from the active site (so-called exosites). The present aim was to shed light on whether the N-terminal tail of the protease domain of FVIIa influences factor X (FX) binding, and whether the zymogen-like conformation of free FVIIa has a decreased affinity for FX compared to the active conformation. Two derivatives of FVIIa, one (FFR-FVIIa) with a stably buried N-terminus representing the active conformation of FVIIa and one (V154G-FVIIa) with a fully exposed N-terminus representing the zymogen-like conformation, were used as inhibitors of FVIIa-catalyzed FX activation. Their inhibitory capacities were very similar, with K(i) values not significantly different from the K(m) for FX. This indicates that the conformational state of the N-terminus does not affect FX binding or, alternatively, that the activation domain including the N-terminal insertion site is easily shifted to the stable conformation ensuing FX docking to the zymogen-like conformation. The net outcome is that FX binding to the zymogen-like form of FVIIa does not appear to be impaired.
Mesh Headings (Keywords): Binding Sites, Enzyme Activation, Enzyme Precursors, Factor VIIa, Factor X, Multiprotein Complexes, Peptide Hydrolases, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Substrate Specificity
Check for Full Text / PubMed Unique Identifier (PMID): 16406236
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