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|Title:||Pathophysiological condition changes the conformation of a flexible FBG-related protein, switching it from pathogen-recognition to host-interaction||Authors:||Zhang, J.
|Keywords:||C-reactive protein (CRP)
Fibrinogen-like domain (FBG)
Fibrinogen-related protein (FREP)
Hydrogen-deuterium exchange mass spectrometry (HDMS)
|Issue Date:||Oct-2011||Citation:||Zhang, J., Yang, L., Anand, G.S., Ho, B., Ding, J.L. (2011-10). Pathophysiological condition changes the conformation of a flexible FBG-related protein, switching it from pathogen-recognition to host-interaction. Biochimie 93 (10) : 1710-1719. ScholarBank@NUS Repository. https://doi.org/10.1016/j.biochi.2011.06.003||Abstract:||Although homeostatic disturbance of the blood pH and calcium in the vicinity of tissue injury/malignancy/local infection seems subtle, it can cause substantial pathophysiological consequences, a phenomenon which has remained largely unexplored. The fibrinogen-related proteins (FREPs) containing fibrinogen-like domain (FBG) represent a conserved protein family with a common calcium-binding region, implying the presence of elements responsive to physiological perturbation. Here, we studied the molecular interaction between a representative FREP, the M-ficolin, and an acute phase blood protein, the C-reactive protein (CRP), both of which are known to trigger and control seminal pathways in infection and injury. Using hydrogen-deuterium exchange mass spectrometry, we showed that the C-terminal region of M-ficolin FBG underwent dramatic conformational change upon pH and calcium perturbations. Biochemical and biophysical assays showed that under defined pathophysiological condition (pH 6.5, 2.0 mM calcium), the FBG:CRP interaction occurred more strongly compared to that under physiological condition (pH 7.4, 2.5 mM calcium). We identified the binding interface between CRP and FBG, locating it to the pH- and calcium-sensitive C-terminal region of FBG. By site-directed mutagenesis, we determined H284 in the N-acetylglucosamine (GlcNAc)-binding pocket of the FBG, to be the critical CRP-binding residue. This conformational switch involving H284, explains how the pathophysiologically-driven FBG:CRP interaction diverts the M-ficolin away from GlcNAc/pathogen-recognition to host protein-protein interaction, thus enabling the host to regain homeostatic control. Our elucidation of the binding interface at the flexible FBG domain provides insights into the bioactive centre of the M-ficolin, and possibly other FREPs, which might aid future development of immunomodulators. © 2011 Elsevier Masson SAS. All rights reserved.||Source Title:||Biochimie||URI:||http://scholarbank.nus.edu.sg/handle/10635/114369||ISSN:||03009084||DOI:||10.1016/j.biochi.2011.06.003|
|Appears in Collections:||Staff Publications|
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