Intrinsically Disordered Proteins (IDP)
Single Molecules to Systems Biology—that was this year’s IDP subgroup symposium’s motto. The exciting program was true to its promise, ranging from visualizing individual proteins with fluorescence methods to a system-wide view of the role of disorder, always with the ultimate goal to improve our knowledge of the repertoire of disordered protein functions in living cells and organisms.
The program got off to a fascinating start when Antoine van Oijen, University of Groningen, described the complex sliding dynamics of single p53 molecules traveling along DNA strands, elucidating the functions of two DNA binding domains of p53, the core binding domain and the disordered C-terminal extension. Jane Dyson, The Scripps Research Institute, next highlighted the power of NMR in the pursuit of molecular mechanisms, in particular showing how IkBa strips the transcriptional activator NFkB from the DNA to form a transcription-inactive complex. Michael Rexach, University of California, Santa Cruz, then presented his “tree and shrub” model of the function of disordered nucleoporins in establishing a selective diffusion barrier in the nuclear pore. Samrat Mukhopadhyay, IISER, Mohali, followed by describing his studies of IDP dynamics and aggregation by a pyrene eximer fluorescence method and near-field scanning optical microscopy. Madan Babu, MRC Laboratory, Cambridge, was the last speaker to take the stage before the break. His systems biology analysis of alternative splicing revealed higher disorder in tissue-specifically spliced exons. These findings may report on fast evolutionary processes that give rise to tissue-specific protein function.
After the break, Eileen Lafer, University of Texas Health Science Center, San Antonio, turned our attention to the role of dynamic disorder and multiple weak binding sites in the clathrin assembly protein AP180—the molecular version of roping in one’s multi-headed bait with a sticky lariat. Jianhan Chen, Kansas State University, then described his use of coarse-grained simulations to shed light on a fundamental question: How do disordered proteins bind to their partners—through conformational selection or induced folding? Doug Barrick, Johns Hopkins University, subgroup chair, next shared his view on the important role of a disordered region in assembly and function of the Notch transcriptional activation complex. Johannes Buchner, Technical University of Munich, closed the symposium with his keynote address. He described a fascinating story on the role of disorder in antibody assembly and a quality control mechanism that takes advantage of coupled binding and folding to ensure secretion of fully assembled and folded antibodies.
In addition, two postdoctoral fellows, Afua Nyarko, Oregon State University, and Martin Stöckl, The University of Twente, received this year’s Postdoctoral Research Awards, which are supported by Molecular Kinetics, and presented short talks during the symposium. Nyarko studied the role of disorder and competing binding sites for mediating binding of dynein to NudE and dynactin.
Stöckl weighed in on the destabilizing effect of alpha-synuclein oligomers on membrane integrity.
–Tanja Mittag and Ashok Deniz
IDP Program Co-Chairs
IDP Program Co-Chairs
Membrane Structure and Assembly The 2012 Membrane Structure and Assembly subgroup symposium was held on February 25. The theme of the symposium was, How Membranes Define Protein Function. The first speaker, Antoinette Killian, University of Utrecht, overviewed the basic principles behind the membrane’s response to inserted peptides. She then discussed how these principles apply to the “minimal sensor” of DesK, a single transmembrane helix protein which responds to membrane thickness and fluidity by altering its catalytic activity. Her talk highlighted the utility of this model system in understanding the effect of the membrane on protein function. She was followed by Emad Tajkhorshid, University of Illinois at Urbana-Champaign, who described 18 april 2012 Biophysical Society Newsletter a novel Highly Mobile Membrane Mimetic (HMMM) model, which represents the lipid molecules by smaller fragments but preserves the interactions in a realistic membrane. Given the enhanced lipid lateral diffusion, the model can be used to study binding and insertion of peptides into membranes very efficiently. The talk emphasized the utility of the model in predicting the spontaneous binding and insertion of coagulation proteins, talin, alpha-synuclein, and viral fusion peptides. Michael Brown, University of Arizona, overviewed the flexiblesurface model (FSM), derived from the balance of curvature and hydrophobic forces in membrane lipidprotein interactions. The FSM can explain the effects of bilayer thickness, nonlamellar-forming lipids, detergents, and osmotic stress on rhodopsin function, as inferred from time-resolved spectrophotometry, solidstate NMR, and FTIR spectroscopy studies. Next, Mark Sansom, University of Oxford, presented multiscale molecular simulations that describe how signaling proteins interact with the lipid membrane and associate to form complexes. He described simulation results for PH domain/PIP interactions, for signaling by integrins, and for PTEN membrane binding. Sin Urban, Howard Hughes Medical Institute and Johns Hopkins University School of Medicine, presented intriguing results demonstrating that the membrane plays a critical role in the function of rhomboid proteases. In particular, he discussed how the rhomboid proteases rely on the natural biophysical constraints of the membrane to achieve site-specific proteolysis. The last speaker of the session was Anne Kenworthy, Vanderbilt Medical Center, who discussed FRAPand FCS-based measurements of protein dynamics in cells, which contribute to our understanding of the properties of toxin-induced domains in living cells.
The scientific session was followed by a business meeting and the members voted on and approved a proposal for a new award in excellence in Membrane Structure and Assembly research named after Thomas E. Thompson. Information about the award is posted online, at the Membrane Structure and Assembly website.
On Sunday night, nine students competed in the membrane structure and assembly category of the SRAA competition. Many thanks to the judges, Edwin Li, St. Joseph’s University, and Alemayehu Gorfe, UT Health Science Center at Houston. Congratulations to the winner, Cynthia Stanich, from the University of Washington.
Now we are looking forward to the 2013 Symposium, to be organized by Heiko Heerklotz, University of Toronto. Looking forward to seeing you in Philadelphia!
–Kalina Hristova, 2012 MSAS Chair
April 2012 Table of Contents