Winner of 2012 FAOBMB Award for Research Excellence: Professor Michael Parker (Australia)
Professor Michael Parker
St Vincent’s Institute of Medical Research, Melbourne, Australia
Michael Parker is an outstanding scientist and leader in his discipline whose original research has had a major impact in biochemistry and molecular biology, in particular structural biology. The major aim of Parker’s research has been to determine the crystal structures of important proteins as a basis for understanding their function as well as exploiting the data for drug discovery. Some of Parker’s seminal contributions have come from the analysis of membrane-associated proteins. He has been a leading international figure in the study of membrane-associating proteins with >100 publications including 11 invited reviews, a book and 6 patents.
Membrane proteins: pore-forming toxins – Among membrane proteins, the pore-forming toxins are unusual because they can exist in a water-soluble state as well as in a membrane-bound state. By focussing initially on the water-soluble forms, Parker was able to avoid many of the difficulties associated with the study of membrane proteins. He predicted – correctly – that the 3D structures of the water-soluble forms would reveal the mechanisms by which pore-forming toxins can create pores in a membrane. His lab determined the structures of several pore-forming toxins establishing himself as a world leader in this field. His methodology for the analysis of membrane protein structures was highlighted in an early topical review by Cowan and Rosenbusch (1994)
In 1997 Parker’s lab determined the first structure of a cholesterol-dependent cytolysin (‘CDC’), perfringolysin O (‘PFO’) from the gas-gangrene-causing bacterium Clostridium perfringens. The structural analysis led to a model for membrane insertion and pore formation, revealing as an extraordinary feature the transition of part of the protein from helix to membrane-spanning sheet. The impact of his work was dramatically demonstrated in 2007 in two papers in Science, which showed that key human immune proteins, involved in defense against invading microorganisms, have 3D structures closely similar to those of the CDCs despite the absence of any sequence homology, thus providing immediate insights into their function. Parker’s work on toxins has been cited > 2,000 times with his recent review on pore-forming toxins being heavily cited, both within and outside the toxin field.
Membrane proteins: Alzheimer’s Disease – Parker’s long-standing interest in protein-membrane interactions led to an interest in how proteins can transmit signals across membranes. In the late nineties he embarked on an ambitious project with Professor Colin Masters (University of Melbourne) to determine the complete structure of amyloid precursor protein (APP), a membrane-bound receptor that plays a central role in Alzheimer’s disease. In one example, he determined the structure of the copper-binding domain that suggested it functions as a metallochaperone. His collaborators showed that copper binding to this domain greatly reduces the abnormal proteolysis of APP and the release of the A-beta peptide that is thought to be a cause of Alzheimer’s disease. The structural information has been used for the structure-based design of therapeutic agents, and resulted in a patent and a commercial relationship with the Prana company.
Membrane proteins: Cytokine receptors – Parker has also developed a strong interest in receptors that bind hormones called cytokines, which then initiate signals inside the cell. For over a decade the hormone-induced receptor dimerisation model served as the textbook paradigm for cytokine receptor activation. This model was based on in vitro studies of the purified extracellular domain of growth hormone receptor. For the first time Parker’s group determined the structure of the apo form of the receptor that revealed no significant change in structure compared to the ligand bound structures. This, together with biophysical and mutagenesis studies performed by Professor Mike Waters (University of Queensland), led to a new model of activation in which the subunits in a preformed dimer undergo a relative rotation on hormone binding. This model may be more generally applicable to other cytokine receptors since it offers rapidity of cell response and allows the cell to respond to very low levels of hormone.
With Professor Angel Lopez (Centre for Cancer Biology, Adelaide), Parker determined the structure of the complete GM-CSF receptor ternary complex in 2008 that revealed a completely unexpected mechanism of signalling. This work showed that cytokine binding in the GM-CSF receptor system can lead to the formation of large oligomers spread over the cell surface allowing great amplification of the biological signal. Subsequent mutagenesis studies by Lopez’s lab demonstrated that the surfaces used to form the oligomers are essential for signalling and that antibodies designed to interact with this surface can inhibit signalling. Thus, the discovery of this interaction surface provides exciting new approaches to develop drugs such as antibodies for fighting certain types of cancer and inflammation. The results of this work have been protected by patent and led to an Options and Licence Agreement with CSL Ltd.