Biophysical Society Newsletter - November 2014

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BIOPHYSICAL SOCIETY NEWSLETTER

2014

NOVEMBER

Biophysical Journal Corner

Know the Editors Jane Dyson

Ashok Deniz Scripps Research Institute Editor for the Proteins and Nucleic Acids Section

Scripps Research Institute

Editor for the Proteins and Nucleic Acids Section

Jane Dyson

Ashok Deniz

Q: What is your area of research? My lab is interested in proteins as self-assembling molecular machines. Many, if not all, proteins will fold into their three-dimensional structures spontaneously: the information that specifies the final folded state is present in the amino acid sequence. We have done a number of experi- ments to determine how the sequence codes for folding, using techniques such as nuclear magnetic resonance (NMR), circular dichro- ism (CD), and fluorescence spectroscopy. Rapid mixing techniques allow us to tease out the steps that occur as a protein folds and to identify the types of amino acids that participate in the initial and later steps of the folding process. Proteins are also versatile and flexible machines, particularly those proteins that we term “intrinsically disor- dered” (IDPs). The signature of an IDP is that it is not folded into a defined three-dimensional structure, but is nevertheless functional. Many IDPs need to be disordered in order to perform their functions, for example, in binding to many different partners (protein or nucleic acid) in the cell. Many important cellular systems contain protein elements that are disordered, and we are beginning to see how this disorder allows the system to function as a molecular machine. The motions of protein chains and their connection with function, for example, in enzymatic reac- tions, is another major effort in the laboratory. Protein dynamics can be measured using NMR experiments such as relaxation dispersion, which gives information on the rates of interconver- sion between states, as well as insights into the population and structure of alternative (invisible) states that are frequently intimately connected with the mechanisms of enzyme catalysis.

Q: What is your area of research? Research at my lab currently focuses on gaining a mechanistic understanding of the physics of protein disorder and complexity, by developing and using cutting-edge tools of single-molecule biophysics. Protein disorder and other complexi- ties are now recognized as integral and function- ally critical components of the biology of the cell. Disordered proteins, however, are dynamic, and exhibit complicated structural and interac- tion biophysics, which makes them difficult to study by conventional tools that typically average information over millions or billions of mol- ecules, thus washing out important information. To avoid this loss of information, we develop and utilize sensitive fluorescence methods that allow us to examine individual molecules. More recently, we have also integrated strengths of novel microfluidic techniques to enhance our experimental capabilities. This powerful set of tools has allowed us to uncover critical new insight, including that (1) some disordered pro- teins populate compact yet rapidly fluctuating structures, (2) interactions can exert fine control over complex, multistate folding-binding energy landscapes, and (3) differential accessibility of disordered protein sequence regions can result in dramatic tunability of binding cooperativity, and consequently cellular function. Our work also lends fundamental insight into aspects of the molecular biophysics of health, for example, in the context of protein misfolding linked to Parkinson’s disease. Overall, our research com- bines insights and tools of physics, chemistry, and biology, and our developed methodologies can be used broadly to investigate functionally important molecular complexity in biology.