Structural biology of complement activation
Our research aims to understand how mammalian hosts defend themselves against pathogenic microorganisms, with a particular focus on a reaction cascade called complement. Complement activates as soon as a pathogen enters the body and serves to neutralise the threat via lysis or opsonisation (where the pathogen is tagged for destruction by host phagocytic cells) and prepare the body against further assault by stimulating and directing inflammatory and adaptive immune responses. Defective complement activation is associated with a wide range of diseases including immunodeficiences, inflammatory disorders (e.g. lupus erythematosus and rheumatoid arthritis), transplant rejection, and ischaemic diseases e.g. of the heart, kidney and brain.
Our research is focused on understanding four main aspects of complement activation at the molecular level: how complement components are able to distinguish between self and non- or altered-self structures; how binding to these structures initiates complement activation; how complement regulators control activation and prevent damage to host tissues and how mutations to complement components lead to disease. Our strategy is to characterise the protein-protein and protein carbohydrate interactions of complement using structural biology (X-ray crystallography, SAXS and EM) and biophysical methods (e.g. ITC, surface plasmon resonance, analytical ultracentrifugation and fluorescence). Our work is carried out in collaboration with Professors Peter Moody (LISCB) and Wilhelm Schwaeble, Department of Respiratory Sciences.
In addition to our work on complement activation, we are also interested in other host-pathogen interactions associated with disease, including the mechanism of action of the pore forming toxin, pnemolysin, of Streptococcus pneumoniae, with Professor Peter Andrew (Respiratory Sciences) and Dr Andrew Hudson (LISCB) and enzymes and signalling pathways of Mycobacterium tuberculosis and Gram +ve bacteria, with Drs Helen O’Hare, Galina Mukamolova, Ed Galyov and Hasan Yesilkaya (Respiratory Sciences).
- Almitairi OM, Venkatraman Girija U,Furze CM, Simpson-Gray X, Badakshi F, Marshall JE, Schwaeble WJ, Mitchell DA, Moody PCE, Wallis R. (2018) Structure of the C1r–C1s interaction of the C1 complex of complement activation. Proc. Natl. Acad. Sci. (USA) 115 (4) 768-773
- Venkatraman Girija U, et al. (2015) 'Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome.' BMC Biol, vol. 13. P. 27.
- Marshall JE, et al. (2015) 'The Crystal Structure of Pneumolysin at 2.0 Å Resolution Reveals the Molecular Packing of the Pre-pore Complex.' Sci Rep, vol. 5. P. 13293.
- Venkatraman Girija U, et al. (2013) 'Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation.' Proc Natl Acad Sci USA, vol. 110. Pp. 13916–13920.
Ahmad Alzamami, Luay Al-Kanan, Jamal Almitairi, Farah Badakshi, Baleeg Kadhim (with Galina Mukamolova) and Zac Newland-Smith (with Helen O’Hare).