Bulletin of the American Physical Society
APS March Meeting 2013
Volume 58, Number 1
Monday–Friday, March 18–22, 2013; Baltimore, Maryland
Session T44: Focus Session: Intrinsically Disordered Proteins |
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Sponsoring Units: DBIO DCP Chair: Daniel Cox, UC Davis Room: Hilton Baltimore Holiday Ballroom 1 |
Thursday, March 21, 2013 8:00AM - 8:36AM |
T44.00001: Connecting sequence to conformational properties of intrinsically disordered proteins Invited Speaker: Rohit Pappu Recent work has shown that intrinsically disordered proteins (IDPs) can be classified as coils or globules based on their net charge per residue (NCPR). Na\"ive annotation of a predictive phase diagram suggests that a majority of IDPs are likely to form disordered globules. Globule formers (as opposed to rigid, folded globules) are likely to have poor solubility profiles and it seems unlikely that the IDP proteome is enriched in globule formers. This raises the possibility that NCPR is an incomplete descriptor of IDP phase behavior. To address this issue, we carried out systematic computational studies on a set of synthetic and naturally occurring IDPs where NCPR is likely to yield questionable designations of IDP phase behavior. Our results show that the polyampholytic nature of IDPs provides a clear descriptor of sequence-ensemble relationships. Our results highlight the connection between linear patterning of oppositely charged residues in polyampholytic sequences and the phase behavior of IDPs / IDRs in sequences where more than 30{\%} of the residues are charged. Analysis of sequence databases shows that $\sim$70{\%} IDPs/IDRs are sequence-patterned polyampholytes that are likely to form heterogeneous expanded ensembles. This has important implications for the accessibility of short linear interaction motifs that directly influence IDP function. [Preview Abstract] |
Thursday, March 21, 2013 8:36AM - 8:48AM |
T44.00002: A Binding Model and Similarity for Flexible Modular Proteins Gabriell M\'at\'e, Christoph J. Feinauer, Andreas Hofmann, Sebastian Goldt, Lei Liu, Dieter W. Heermann Modular proteins are one of the most commonly found disordered protein motifs. An example is CTCF, a protein that has been named the master waver of the genome i.e., the organizer of the 3D structure of the chromosomes. Using NMR and numerical simulations, much progress has been made in understanding their various functions and ways of binding. Modular proteins are often composed of protein modules interconnected by flexible linkers. They can be imagined as ``beads on a string.'' We argue that when the number of beads is small, these structures behave like a self avoiding random walk. Nevertheless, when binding to a target, linkers can fold in more ordered and stable states. At the same time, folding can influence functional roles. We show that the flexibility of the linkers can boost binding affinity. As a result of flexibility, the conformations of these proteins before and after binding are different. So this implies that generic binding site prediction methods may fail. To deal with this we introduce a new methodology to characterize and compare these flexible structures. Employing topological concepts we propose a method which intrinsically fuses topology and geometry. [Preview Abstract] |
Thursday, March 21, 2013 8:48AM - 9:00AM |
T44.00003: Spatial clustering of binding motifs and charges reveals conserved functional features in disordered nucleoporin sequences David Ando, Michael Colvin, Michael Rexach, Ajay Gopinathan The Nuclear Pore Complex (NPC) gates the only channel through which cells exchange material between the nucleus and cytoplasm. Traffic is regulated by transport receptors bound to cargo which interact with numerous of disordered phenylalanine glycine (FG) repeat containing proteins (FG nups) that line this channel. The precise physical mechanism of transport regulation has remained elusive primarily due to the difficulty in understanding the structure and dynamics of such a large assembly of interacting disordered proteins. Here we have performed a comprehensive bioinformatic analysis, specifically tailored towards disordered proteins, on thousands of nuclear pore proteins from a variety of species revealing a set of highly conserved features in the sequence structure among FG nups. Contrary to the general perception that these proteins are functionally equivalent to homogeneous polymers, we show that biophysically important features within individual nups like the separation, spatial localization and ordering along the chain of FG and charge domains are highly conserved. Our current understanding of NPC structure and function should therefore be revised to account for these common features that are functionally relevant for the underlying physical mechanism of NPC gating. [Preview Abstract] |
Thursday, March 21, 2013 9:00AM - 9:12AM |
T44.00004: Molecular Dynamics Simulations of the Fluctuating Conformational Dynamics of the Intrinsically Disordered Proteins $\alpha$-Synuclein and $\tau$ W. Wendell Smith, Carl Schreck, Abhinav Nath, Elizabeth Rhoades, Corey O'Hern Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop united-atom and coarse-grained Langevin dynamics simulations for the IDPs $\alpha$-synuclein and $\tau$ that include geometric,attractive hydrophobic, and screened electrostatic interactions and are calibrated to the inter-residue separations measured in recent smFRET experiments. We find that these IDPs have conformational statistics that are intermediate between random walk and collapsed globule behavior and demonstrate close resemblance to the known experimental data, with both electrostatics and hydrophobicity strongly influencing the dynamics. We investigate the propensity of $\alpha$-synuclein to aggregate and form oligomers, and present preliminary results for the aggregation of $\tau$ and interactions between these IDPs and small molecules such as heparin and spermine which are known to induce aggregation. [Preview Abstract] |
Thursday, March 21, 2013 9:12AM - 9:48AM |
T44.00005: Intrinsically disordered segments and the evolution of protein half-life Invited Speaker: M. Madan Babu Precise turnover of proteins is essential for cellular homeostasis and is primarily mediated by the proteasome. Thus, a fundamental question is: What features make a protein an efficient substrate for degradation? Here I will present results that proteins with a long terminal disordered segment or internal disordered segments have a significantly shorter half-life in yeast. This relationship appears to be evolutionarily conserved in mouse and human. Furthermore, upon gene duplication, divergence in the length of terminal disorder or variation in the number of internal disordered segments results in significant alteration of the half-life of yeast paralogs. Many proteins that exhibit such changes participate in signaling, where altered protein half-life will likely influence their activity. We suggest that variation in the length and number of disordered segments could serve as a remarkably simple means to evolve protein half-life and may serve as an underappreciated source of genetic variation with important phenotypic consequences. [Preview Abstract] |
Thursday, March 21, 2013 9:48AM - 10:24AM |
T44.00006: Structural transitions in the intrinsically disordered Parkinson's protein alpha-synuclein Invited Speaker: David Eliezer The protein alpha-synuclein is genetically and histopathologically associated with familial and sporadic Parkinson's disease. Although considered to belong to the category of intrinsically disordered proteins for well over a decade, recent reports have suggested that synuclein may actually exist predominantly in a native, well-structured, tetrameric form. Experiments using in-cell NMR, which bypass potential structural perturbations caused by purification protocols, conclusively demonstrate that recombinant synuclein is in fact highly disordered and monomeric. In the presence of membranes, however, the protein undergoes a coil-to-helix transition to adopt several highly helical conformations, which are proposed to mediate both its normal function and its membrane-induced aggregation into amyloid fibrils. [Preview Abstract] |
Thursday, March 21, 2013 10:24AM - 10:36AM |
T44.00007: Dimer model for Tau proteins bound in microtubule bundles Natalie Hall, Alexander Kluber, N. Robert Hayre, Rajiv Singh, Daniel Cox The microtubule associated protein tau is important in nucleating and maintaining microtubule spacing and structure in neuronal axons. Modification of tau is implicated as a later stage process in Alzheimer's disease, but little is known about the structure of tau in microtubule bundles. We present preliminary work on a proposed model [1] for tau dimers in microtubule bundles (dimers are the minimal units since there is one microtubule binding domain per tau). First, a model of tau monomer was created and its characteristics explored using implicit solvent molecular dynamics simulation. Multiple simulations yield a partially collapsed form with separate positively/negatively charged clumps, but which are a factor of two smaller than required by observed microtubule spacing. We argue that this will elongate in dimer form to lower electrostatic energy at a cost of entropic ``spring'' energy. We will present preliminary results on steered molecular dynamics runs on tau dimers to estimate the actual force constant.\\[4pt] [1] Rosenberg, K. J. Ross, J. L. Feinstein, H. E., Feinstein, S. C. Israelachvili, J., PNAS (USA) 105, 2008, 7445-50. [Preview Abstract] |
Thursday, March 21, 2013 10:36AM - 10:48AM |
T44.00008: Physical modeling of the conformation of the unfolded proteins of the Nuclear Pore Complex Anton Zilman, Michael Opferman, Rob Coalson, David Jasnow Nuclear Pore Complex (NPC) is a biological ``nano-machine'' that controls the macromolecular transport between the cell nucleus and the cytoplasm. NPC functions without direct input of metabolic energy and without transitions of the gate from a ``closed'' to an ``open'' state during transport. The key and unique aspect of transport is the interaction of the transported molecules with the unfolded, natively unstructured proteins that cover the lumen of the NPC. Recently, the NPC inspired creation of artificial bio-mimetic for nano-technology applications. Although several models have been proposed, it is still not clear how the passage of the transport factors is coupled to the conformational dynamics of the unfolded proteins within the NPC. Morphology changes in assemblies of the unfolded proteins induced by the transport factors have been investigated experimentally in vitro. I will present a coarse-grained theoretical and simulation framework that mimics the interactions of unfolded proteins with nano-sized transport factors. The simple physical model predicts morphology changes that explain the recent puzzling experimental results and suggests possible new modes of transport through the NPC. It also provides insights into the physics of the behavior of unfolded proteins. [Preview Abstract] |
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