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Structural studies of SCR domains in multidomain complement proteins

Aslam, Mohammed; (2003) Structural studies of SCR domains in multidomain complement proteins. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

There is a level of organization in proteins that overlaps the classical definitions of tertiary and quaternary structure, i.e. sequentially consecutive residues in polypeptide chains fold into distinct independently-folded regions called domains. Many multidomain proteins are flexible at their interdomain junctions and are therefore not amenable to X-ray crystallography or are too big for multinuclear NMR techniques. Small-angle X-ray and neutron scattering and analytical centrifugation methods, coupled with molecular modelling techniques, are able to locate the relative positions of these domains relative to each other within the full protein structure. This PhD thesis has looked at the short complement/consensus repeat (SCR) domains of two complement proteins, Factor H (FH) and complement related protein y (Crry) in order to identify the principles of their domain arrangement. SCR domains are widespread in complement proteins and the solution conformation between adjacent SCR pairs is central to the understanding of the molecular mechanism of complement activation. A method of scattering curve modelling based on rigid body structures as constraints provide medium resolution structures on the solution structure of these SCR proteins. Using an automated constrained fit procedure, with complement FH, only those models in which the 20 SCR domains in FH were bent back upon themselves were able to account for the scattering and sedimentation data. These bent-back FH structures may permit the multiple binding sites for C3 and heparin to come into close proximity, and assist the multifunctional role of FH. It is concluded that, if the inter SCR linkers are as long as eight residues, as found in human FH, significant flexibility and the generation of folded back structures can result. If the inter SCR linkers are of short length, this results in only a modest degree of bending and this was observed in rodent Crry. The averaged solution structure of Crry with five SCR domains was found to be highly extended with a slightly bent arrangement of SCR domains. The structural models for FH and Crry have been useful in the elucidation of the consequences of mutations e.g. FH in haemolytic uraemic syndrome and the evaluation of anti-inflammatory therapeutic reagents based on Crry that suppress complement activation.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Structural studies of SCR domains in multidomain complement proteins
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Biological sciences; SCR domains
URI: https://discovery.ucl.ac.uk/id/eprint/10102811
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