Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.biochi.2011.06.003
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dc.titlePathophysiological condition changes the conformation of a flexible FBG-related protein, switching it from pathogen-recognition to host-interaction
dc.contributor.authorZhang, J.
dc.contributor.authorYang, L.
dc.contributor.authorAnand, G.S.
dc.contributor.authorHo, B.
dc.contributor.authorDing, J.L.
dc.date.accessioned2014-12-02T06:53:09Z
dc.date.available2014-12-02T06:53:09Z
dc.date.issued2011-10
dc.identifier.citationZhang, 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
dc.identifier.issn03009084
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/114369
dc.description.abstractAlthough 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.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1016/j.biochi.2011.06.003
dc.sourceScopus
dc.subjectC-reactive protein (CRP)
dc.subjectConformational change
dc.subjectFibrinogen-like domain (FBG)
dc.subjectFibrinogen-related protein (FREP)
dc.subjectHydrogen-deuterium exchange mass spectrometry (HDMS)
dc.typeArticle
dc.contributor.departmentBIOLOGICAL SCIENCES
dc.contributor.departmentSINGAPORE-MIT ALLIANCE
dc.description.doi10.1016/j.biochi.2011.06.003
dc.description.sourcetitleBiochimie
dc.description.volume93
dc.description.issue10
dc.description.page1710-1719
dc.description.codenBICMB
dc.identifier.isiut000295107700010
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