Nigel Robinson (Biology & Chemistry, Durham University, UK)
Abstract: ‘For you to be here now, trillions of drifting atoms have come together in an intricate and curiously obliging manner to create you. Why atoms take the trouble is a bit of a puzzle’ (adapted from the opening lines of ‘A short history of nearly everything’ by Bill Bryson). Among the gathered atoms are essential metals including magnesium, calcium, molybdenum, manganese, iron, cobalt, copper and zinc. These metals are required as cofactors for proteins, and in other processes. From bioinformatics studies of Lucia Banci and co-workers, we can begin to infer that a half of enzyme-types require at least one of these atoms. Metals increase the repertoire of reactions beyond what is easily achieved using carbon, nitrogen, hydrogen and sulphur alone. Ensuring that metals are present in the correct amounts (the cell quotas described by Tom O'Halloran) and come together with desirable partners are major biological challenges. The latter challenge is exacerbated because most proteins prefer to bind one or more incorrect metals more tightly than the correct ions. To meet this challenge cells are thought to control the buffered, exchangeable concentrations of each metal as an inverse function of how tightly the metals bind. Proteins then compete with other proteins for a limited pool of the most competitive metals such as copper and nickel, rather than metals competing with other metals for a limited pool of protein. In contrast, the least competitive essential metals such as magnesium can be present in excess without causing harm. All four of todays' speakers have contributed to defining the buffered metal concentrations in cells including, for example, by developing and using fluorescent probes to interrogate copper (Christoph Fahrni) and zinc (Tom O'Halloran) pools. The polydisperse metal-pools of cells are chemically complex, but todays' session will explore whether they may be better defined through mathematics. Maintaining competitive metals such as copper and nickel at ultra-low concentrations solves one challenge but creates another by limiting chance encounters with proteins which do require these ions. Todays' speakers include the pioneers who have discovered, defined and characterised a class of proteins, metallochaperones, which deliver metals such as copper or nickel to the correct destinations, potentially overcoming the second challenge. Can mathematics better define the flux of metals via ligand exchange reactions along such delivery pathways? Cells maintain the buffered metal-pools at the correct concentrations through the combined actions of metal-import proteins, -export proteins, -storage proteins and by switching metabolism to exploit surplus ions and minimise demand for deficient ones: all processes controlled by metal-sensors: But this apparent solution really just ‘passes-the-buck’ from the metallo-enzymes to the proteins of metal homeostasis. The question now becomes how do proteins of metal-homeostasis select the correct metals? Why don't they simply bind the most competitive ions? A further purpose of the session is to explore how mathematics may help to solve this part of the puzzle: For example to piece-together the multiple coupled-reactions of metal-sensors, being defined by David Giedroc.
[1] Tottey, S., Patterson, C.J., Banci, L., Bertini, I., Felli, I.C., Pavelkova, A., Dainty, S.J., Pernil, R., Waldron, K.J., Foster, A.W., Robinson, N.J. (2012), Cyanobacterial metallochaperone inhibits deleterious side reactions of copper, PNAS 109: 95-100.
[2] Foster, A.W., Patterson, C.J., Pernil, R., Hess, C.R., Robinson, N.J. (2012), A cytosolic Ni(II) sensor in a cyanobacterium: Nickel-detection follows nickel-affinity across four families of metal-sensors, Journal of Biological Chemistry 287: 12142-12151.
[3] Robinson, N.J, Winge D.R. (2010), Copper metallochaperones, Annual Review of Biochemistry 79: 537-562;
Waldron, K.J, Rutherford, J.C, Ford, D. & Robinson, N.J. (2009), Metalloproteins and metal-sensing, Nature 460: 823-830 {listen to the linked podcast for a further introduction}.
[4] Tottey, S, Waldron, K.J, Firbank, S.J, Reale, B, Bessant, C, Sato, K, Cheek, T.R, Gray, J, Banfield, M.J, Dennison C. & Robinson, N.J. (2008), Protein-folding location can regulate manganese-binding versus copper- or zinc-binding, Nature 455: 1138-1142.