Dr David Gell
ARC Australian Research Fellow G08 - Biochemistry and Microbiology Building
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We aim to understand regulatory protein interactions at the molecular level.
We use a range of molecular and biophysical methods to investigate proteins and their interactions. Methods include, but are not limited to, NMR spectroscopy and many other spectroscopic techniques, mutational analysis, recombinant protein production and purification, microcalorimetry, analytical ultracentrifugation and yeast 2-hybrid. Our approach is to find the right technique to solve the particular biological problem that we are currently addressing and we have many collaborators from within the department and elsewhere in the University of Sydney and beyond.
One of our current area of research is the regulation of haemoglobin in mammalian systems. Haemoglobin (Hb) is a tetramer of α- and β-Hb subunits and disorders leading to imbalances in subunit production can create serious illness (thalassaemia). We have described a new mechanism by which assembly of Hb subunits is facilitated through direct protein:protein interaction with a newly discovered factor, α-Hb stabilising protein (AHSP). AHSP binds specifically to α-Hb that has not yet been incorporated into Hb tetramer and prevents its precipitation. At the mechanistic level, the AHSP:α-Hb complex inhibits the formation of damaging free radicals generated by reaction of dissolved oxygen species with the αHb Fe atom. It does this by inducing a conformational change in α-Hb such that the haem-Fe becomes bound in both available reaction sites by two histidine side chains from the α-Hb protein.This work will contribute to our understanding of oxidative damage in the circulatory system and may have significance for blood conditions such as thalassaemias.
We use a range of molecular and biophysical methods to investigate proteins and their interactions. Methods include, but are not limited to, NMR spectroscopy and many other spectroscopic techniques, mutational analysis, recombinant protein production and purification, microcalorimetry, analytical ultracentrifugation and yeast 2-hybrid. Our approach is to find the right technique to solve the particular biological problem that we are currently addressing and we have many collaborators from within the department and elsewhere in the University of Sydney and beyond.
One of our current area of research is the regulation of haemoglobin in mammalian systems. Haemoglobin (Hb) is a tetramer of α- and β-Hb subunits and disorders leading to imbalances in subunit production can create serious illness (thalassaemia). We have described a new mechanism by which assembly of Hb subunits is facilitated through direct protein:protein interaction with a newly discovered factor, α-Hb stabilising protein (AHSP). AHSP binds specifically to α-Hb that has not yet been incorporated into Hb tetramer and prevents its precipitation. At the mechanistic level, the AHSP:α-Hb complex inhibits the formation of damaging free radicals generated by reaction of dissolved oxygen species with the αHb Fe atom. It does this by inducing a conformational change in α-Hb such that the haem-Fe becomes bound in both available reaction sites by two histidine side chains from the α-Hb protein.This work will contribute to our understanding of oxidative damage in the circulatory system and may have significance for blood conditions such as thalassaemias.
- Yu, X, Kong, Y, Dore, L, Abdulmalik, O, Katein, A, Zhou, S, Choi, J, Gell, D, Mackay, J, Gow, A, Weiss, M. An erythroid chaperone that facilitates folding of alpha-globin subunits for hemoglobin synthesis. The Journal of clinical investigation. 2007; 117:1856-65 [Abstract]
- Gell, D, Westman, B, Gorman, D, Liew, C, Welch, J, Weiss, M, Mackay, J. A Novel Haem-binding Interface in the 22 kDa Haem-binding Protein p22HBP. Journal of molecular biology. 2006; 362:287-97 [Abstract]
- Feng, L, Zhou, S, Gu, L, Gell, D, Mackay, J, Weiss, M, Gow, A, Shi, Y. Structure of oxidized alpha-haemoglobin bound to AHSP reveals a protective mechanism for haem. Nature. 2005; 435:697-701 [Abstract]
- Weiss, M, Zhou, S, Feng, L, Gell, D, Mackay, J, Shi, Y, Gow, A. Role of Alpha Hemoglobin-Stabilizing Protein in Normal Erythropoiesis and {beta}-Thalassemia. Annals of the New York Academy of Sciences. 2005; 1054:103-17 [Abstract]
- Feng, L, Gell, D, Zhou, S, Gu, L, Kong, Y, Li, J, Hu, M, Yan, N, Lee, C, Rich, A, Armstrong, R, Lay, P, Gow, A, Weiss, M, Mackay, J, Shi, Y. Molecular mechanism of AHSP-mediated stabilization of alpha-hemoglobin. Cell. 2004; 119:629-40 [Abstract]
- Kong, Y, Zhou, S, Kihm, A, Katein, A, Yu, X, Gell, D, Mackay, J, Adachi, K, Foster-Brown, L, Louden, C, Gow, A, Weiss, M. Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia. The Journal of clinical investigation. 2004; 114:1457-66 [Abstract]
- Kwan, A, Gell, D, Verger, A, Crossley, M, Matthews, J, Mackay, J. Engineering a protein scaffold from a PHD finger. Structure (London, England : 1993). 2003; 11:803-13 [Abstract]
- Gell, D, Kong, Y, Eaton, S, Weiss, M, Mackay, J. Biophysical characterization of the alpha-globin binding protein alpha-hemoglobin stabilizing protein. The Journal of biological chemistry. 2002; 277:40602-9 [Abstract]
- Westman, B, Mackay, J, Gell, D. Ikaros: a key regulator of haematopoiesis. The international journal of biochemistry & cell biology. 2002; 34:1304-7 [Abstract]
- Kowalski, K, Liew, C, Matthews, J, Gell, D, Crossley, M, Mackay, J. Characterization of the conserved interaction between GATA and FOG family proteins. The Journal of biological chemistry. 2002; 277:35720-9 [Abstract]
- Sharpe, B, Matthews, J, Kwan, A, Newton, A, Gell, D, Crossley, M, Mackay, J. A new zinc binding fold underlines the versatility of zinc binding modules in protein evolution. Structure (London, England : 1993). 2002; 10:639-48 [Abstract]
Heme; Blood Proteins; Hemoglobin A; Oxyhemoglobins