Smith, David - Sheffield Hallam University - Department of Biosciences and Chemistry

个人简介

David teaches Molecular Biology and Biochemistry at both Undergraduate and Postgraduate level and is a Senior Fellow of the Higher Education Academy. He has been awarded the Sheffield Hallam Inspirational Teacher Awards three times.

研究领域

David's research interests are centred on understanding why some proteins change their shape to bring about disease. To investigate this I use Electrospray ionisation - ion mobility spectrometry - mass spectrometry in the context of Parkinson's disease. Using new neural cell culture models to study the prion-like spread of Parkinson’s disease pathology. Metal Homeostasis, Phosphorylation and the Effect on the Aggregation of α-synuclein Investigating the dynamics and assembly of alpha-synuclein amyloid oligomers by electrospray ionisation-ion mobility-mass spectrometry Labelled IMS TAG Proteins for Quantitative Mass Spectrometry Imaging Ion mobility spectrometry - mass spectrometry Electrospray ionisation - ion mobility spectrometry - mass spectrometry (ESI-IMS-MS) is an emerging technique and can be utilised to characterise the conformational states of monomeric proteins and large non-covalent complexes. ESI-IMS-MS has the unique advantage of allowing the structural characterisation of transient non-covalent protein complexes and co-populated conformational states to be monitored in real time. Detailed knowledge of the tertiary and quaternary structure of proteins and protein complexes is of immense importance in understanding their functionality. Similarly, variations in the conformational states of proteins underlie many biomolecular processes, numerous of which are disease-related, for example, cystic fibrosis; some forms of cancer; and the amyloid diseases including Alzheimer's, Parkinson's and CJD. Parkinson's disease Parkinson's disease (PD) is the most common neurodegenerative disorder after Alzheimer's disease affecting 1 in 500 of the UK population. Although rare heritable forms of the disease have been documented, the sporadic form is far more common and possibly connected to environmental factors that promote oxidative stress and aberrant metal-mediated redox chemistry. A critical step in the aetiology of PD is the formation of Lewy bodies in which aggregated alpha-synuclein in the form of amyloid-like aggregates has been identified as a major component and transiently populated alpha-synuclein oligomers have been implicated as the causative agent in PD. Alternate oligomeric forms have been identified with differing biochemical characteristics, yet little is known about their structural characteristics. David's research is based around understanding the structure and toxic function of these oligomers ESI-IMS-MS is used to assess the size (molecular weight) and shape distribution (CCS) of the oligomers and any covalent modification to the protein. By comparison with models, estimates of the degree of compactness and general shape adopted by the oligomers is possible. Changes in the size and structure of these oligomers is also measured as a function of aggregation and amyloid formation. Through this work the structural and conformation of differing forms of alpha-synuclein oligomers as well as the effect of phosphorylation and metal binding will be addressed. The results gained will raise the possibility of intervention via small molecule inhibition, as differences between toxic and non-toxic oligomeric forms are identified.

近期论文

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ILLES-TOH, E, RAMOS, MR, CAPPAI, R, DALTON, CF and SMITH, DP (2015). Structural characterisation of oligomeric alpha-synuclein by ion mobility spectrometry mass spectrometry. Biochem J.(doi:10.1042/BJ20150159) KRIECHBAUMER, V, NABOK, A, MUSTAFA, MK, AL-AMMAR, R, SMITH, DP, ABELL, BM (2011) Biophysical analysis of receptor protein interactions observed in situ on native chloroplast membranes via total internal reflection ellipsometry. PLoS One. 2012;7(3):e34455. Epub 2012 Mar 29. SMITH, DP, WOODS, LA, RADFORD, SE, ASHCROFT, AE (2011). Structure and dynamics of oligomeric intermediates in β2-microglobulin self-assembly. Biophysical Journal MASON, Rebecca, PASKINS, Aimee, DALTON, Caroline and SMITH, David (2016). Copper Binding and Subsequent Aggregation of α-Synuclein Are Modulated by N-Terminal Acetylation and Ablated by the H50Q Missense Mutation. Biochemistry, 55 (34), 4737-4741. SMITH, David P. (2016). Active learning in the lecture theatre using 3D printed objects. F1000Research, 5 (61), 1-18. HARVEY, Amanda, DAY, Rebecca, COLE, Laura M., BARTLETT, Maggie, WARWICK, John, BOJAR, Richard, SMITH, David, CROSS, Neil and CLENCH, Malcolm R. (2016). MALDI-MSI for the analysis of a 3D tissue-engineered psoriatic skin model. Proteomics, 16 (11-12), 1718-1725.