Protein folding, function and engineering

点击翻译按钮获取中文摘要

Proteins are the molecular machines of life, performing a huge range of functions, from acting as catalysts, to specifically recognizing and binding other molecules, to structural support roles. The order of amino acids in a protein, i.e. its primary sequence, encodes how the protein folds into its functional "native" structure. Despite extensive study, the mechanisms by which primary sequence determines protein folding and function remain unclear. Understanding these mechanisms is of tremendous importance because, ultimately, such an understanding will give us the ability to rationally predict the behaviour of any protein (such as a misfunctional mutant protein that causes disease). It will also give us the ability to engineer or design proteins for any desired application in biotechnology or medicine. Tremendous recent advances in knowledge of protein sequences and in protein modeling have set the stage for making dramatic advances in understanding how sequence determines folding and function. For example, we used sequence information and modeling successfully to engineer the first completely 3-fold symmetric globular protein, called ThreeFoil, which is extremely stable and has sugar binding functionality. Since many protein engineering attempts fail, sometimes in subtle ways, we now need to analyze ThreeFoil further to fully understand the outcome of our engineering. We also propose to extend our studies on ThreeFoil to related proteins, including other types of natural and designed symmetric proteins. One of these, called Hisactophilin, plays a central role in controlling the movement of cells by its reversible binding to cell membranes and other cytoskeletal proteins in response to pH signals generated by the cell's environment. We are using Hisactophilin as a model to understanding signaling and regulated, reversible binding by proteins. We are also studying the damaging effects of ultrasound on these and other proteins, which is important for many applications of ultrasound for industrial and medical applications. Together, our in depth studies will lead to important new knowledge on how proteins work and how they can be controlled.