Venkatraman Girija, Umakhanth, Furze, Christopher, Toth, Julia, Schwaeble, Wilhelm W., Mitchell, Daniel Anthony, Keeble, Anthony H. and Wallis, Russell. (2010) Engineering novel complement activity into a pulmonary surfactant protein. Journal of Biological Chemistry, Vol.285 (No.10). pp. 546-552. ISSN 0021-9258

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Abstract

Complement neutralizes invading pathogens, stimulates inflammatory and adaptive immune responses, and targets non- or altered-self structures for clearance. In the classical and lectin activation pathways, it is initiated when complexes composed of separate recognition and activation subcomponents bind to a pathogen surface. Despite its apparent complexity, recognition-mediated activation has evolved independently in three separate protein families, C1q, mannose-binding lectins (MBLs), and serum ficolins. Although unrelated, all have bouquet-like architectures and associate with complement-specific serine proteases: MBLs and ficolins with MBL-associated serine protease-2 (MASP-2) and C1q with C1r and C1s. To examine the structural requirements for complement activation, we have created a number of novel recombinant rat MBLs in which the position and orientation of the MASP-binding sites have been changed. We have also engineered MASP binding into a pulmonary surfactant protein (SP-A), which has the same domain structure and architecture as MBL but lacks any intrinsic complement activity. The data reveal that complement activity is remarkably tolerant to changes in the size and orientation of the collagenous stalks of MBL, implying considerable rotational and conformational flexibility in unbound MBL. Furthermore, novel complement activity is introduced concurrently with MASP binding in SP-A but is uncontrolled and occurs even in the absence of a carbohydrate target. Thus, the active rather than the zymogen state is default in lectin·MASP complexes and must be inhibited through additional regions in circulating MBLs until triggered by pathogen recognition.

Item Type:	Journal Article
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Divisions:	Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Complement activation, Enzyme activation, Protein-protein interactions -- Research, Lectins -- Research, Immunochemistry -- Research, Proteolytic enzymes, Collagen
Journal or Publication Title:	Journal of Biological Chemistry
Publisher:	American Society for Biochemistry and Molecular Biology, Inc.
ISSN:	0021-9258
Date:	2 April 2010
Volume:	Vol.285
Number:	No.10
Page Range:	pp. 546-552
Identification Number:	10.1074/jbc.M109.097493
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Wellcome Trust (London, England), Medical Research Council (Great Britain) (MRC), Research Councils UK (RCUK)
Grant number:	077400 (Wellcome), G0501425 (MRC)
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URI:	http://wrap.warwick.ac.uk/id/eprint/3009

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