2020AlmitairiJOMPhD.pdf (5 MB)

Characterisation of the classical and lectin pathways of complement activation and the roles of complement inhibitors LAIR-2 and BBK32

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thesis
posted on 05.08.2020, 11:03 by Jamal O. Almitairi
The complement system is part of innate immunity and fights invading pathogens via opsonisation and cell lysis. Three pathways activate complement: the classical (CP), the lectin (LP) and the alternative pathway (AP). The CP is initiated by a multimeric 790 kDa complex named C1. This complex is formed from a hexameric, bouquet-like protein called C1q assembled from three polypeptide chains A, B and C and four associated serine proteases; two C1r and two C1s, as a Ca2+-dependant heterotetramer. C1r and C1s are homologous modular proteases composed of an N-terminal CUB1 domain, followed by an EGF-like domain, a CUB2 domain followed by two CCP modules, and a serine protease domain (SP). Several models have been proposed to explain how C1 is assembled. In this thesis I have determined the crystal structure of the C1r-C1s complex and propose a detailed model for assembly of C1. In this model, C1r2C1s2 complexes adopt an extended S-shaped structure that fold up to form a more compact structure when binding to C1q. Additional crystal structures of a fragment of C1s in complex with collagen-like peptides derived from the A, B and C chains of C1q suggest that C1qC is the leading chain and C1qA is the middle and C1qB is the lagging chain in each collagen-like domain. I also characterised the role of the immune modulator LAIR-2 in downregulating the activation of the CP and LP. Data reported here shows that LAIR-2 binds to the collagen like domain of MBL and thereby regulates activation of the LP. Finally, I assessed the interaction between the Borrelia burgdorferi surface protein BBK32 and C1r. Previous studies have suggested that BBK32 inhibits the CP by binding to C1r-CUB1-EGF-CUB2. However, the data reported here shows no interaction between BBK32 and C1r-CUB1-EGF-CUB2 domains.

History

Supervisor(s)

Russell Wallis

Date of award

13/07/2020

Author affiliation

Department of Infection, Immunity and Inflammation

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

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