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Title: Complement-carbohydrate interactions : studies of mannose binding lectin and complement factor H
Author: Miller, A.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2012
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The complement system is a fundamental component of innate immunity that orchestrates complex immunological and inflammatory processes. Complement comprises over 30 proteins that eliminates invading microorganisms while maintaining host cell integrity. Protein-carbohydrate interactions play critical roles in both the activation and regulation of complement. Mannose binding lectin (MBL) activates the lectin pathway of complement via the recognition of sugar arrays on pathogenic surfaces. X-ray scattering and AUC combined with constrained modelling were used to identify a bent structure for the MBL monomer in terms of crystal structures for its carbohydrate-recognition domain and its triple helical region. Near-planar solution structures were determined for the MBL dimer, trimer and tetramer. These solution structures clarified how MBL binds to pathogenic surfaces and provides a template for the binding and autoactivation of the MASP protease to initiate the lectin pathway of complement activation. Factor H (FH) with 20 short complement regulator (SCR) domains regulates the alternative pathway of complement by facilitating the breakdown of the central component C3b. FH binds to heparan sulphate (HS) and to heparin (a HS analogue) on host cell surfaces where it regulates C3b activity and protects these cells from complement attack. A Tyr402His polymorphism in SCR-7 is a major risk factor for the development of age-related macular degeneration (AMD), and is involved in heparin binding. Both the Tyr402 and His402 allotypes of the SCR-6/8 fragment of FH were cloned and expressed in an E. coli system. X-ray scattering, analytical ultracentrifugation and surface plasmon resonance were used to characterise the interactions of FH Tyr402 and His402 with heparin and HS. These polyanions induce the strong self-association of FH SCR-6/8, the extent of which was found to be dependent on the length of the polyanion and the presence of the His402 allotype. The formation of large FH-heparin aggregates may provide a molecular explanation for the link between the Tyr402His polymorphism and the initial formation of drusen deposits in AMD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available