The complement system is part of our innate immune response and is tightly regulated to prevent damage to host cells. Complement receptor type 1 (CR1) is one of the main regulators of complement activation and is also the immune adherance receptor on erythrocytes, important for clearance of immune complexes from the bloodstream. CR1s functions arise from its ability to bind complement proteins C3b and C4b. CR1 is a multimodular glycoprotein (220 kDa) that is too large to study in its intact form by NMR. Recently, the solution structure of functional site 2, which consists of three contiguous complement control protein (CCP) modules, has been solved. However, the structural information alone does not complete the story as dynamic motions within CR1 are likely to have implications for its functions. This thesis describes the assignment of 15N and 1H NMR data for the central CCP module (module 16) of functional site 2. The resonance assignments subsequently allowed the solution 3D structure to be determined and the Modelfree analysis of the module’s isotropic dynamics. The structure and dynamics of the lone module, when compared with previous work on larger fragments of functional site 2 allowed assessment of the importance, for their structure and flexibility, of the context of CCP modules. Following this, NMR 13C, 15N and 1H spectra for CR1 modules 2-3, which correspond to the C-terminal two thirds of functional site 1, were acquired. The resonance assignment of this double module was then performed to near completion. In parallel, a homology-based model of the structure of modules 2-3 was built using the structure of site 2 as a starting point. The isotropic dynamics were also analysed using Modelfree formalism.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:641674 |
| Date | January 2004 |
| Creators | Black, Gordon M. |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/10824 |
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