Bulletin of the American Physical Society
APS March Meeting 2019
Volume 64, Number 2
Monday–Friday, March 4–8, 2019; Boston, Massachusetts
Session V51: Protein Liquid-Liquid Phase SeparationInvited
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Sponsoring Units: DBIO DPOLY Chair: Xiaoqin Zou, University of Missouri Room: BCEC 253A |
Thursday, March 7, 2019 2:30PM - 3:06PM |
V51.00001: Physical Basis of Protein Liquid-Liquid Phase Separation Invited Speaker: Huan-Xiang Zhou Intracellular membraneless organelles, corresponding to the droplet phase upon liquid-liquid phase separation (LLPS) of mixtures of proteins and possibly RNA, mediate myriad cellular functions [Qin & Zhou 2017 Curr Opin Struct Biol]. Cells use a variety of biochemical signals such as expression level and posttranslational modification to regulate droplet formation and dissolution. Our study focuses on elucidating the physical basis of phase behaviors associated with cellular functions of membraneless organelles, using three complementary approaches. First, we use colloids and polymers, respectively, as models for structured and disordered proteins, to investigate both the common basis for protein phase separation and the unique characteristics of structured and disordered proteins in LLPS [Zhou et al 2018 Trends Biochem Sci]. Disordered proteins are characterized by both extensive attraction throughout the sequence and low energetic cost from steric repulsion, contributing to easy observation of phase separation. Second, we use multi-component patchy particles to investigate the wide range of effects of regulatory components on the droplet formation of driver proteins [Nguemaha & Zhou 2018 Sci Rep]. Third, we have developed a powerful computational method called FMAP for determining liquid-liquid phase equilibria [Qin & Zhou 2014 J Chem Theory Comput; 2016 J Phys Chem B]. By using fast Fourier transform to efficiently evaluate protein-protein interactions, FMAP enables an atomistic representation of the protein molecules. Application to g-crystalins reveals how minor variations in amino-acid sequence, similar to those from posttranslational modifications and disease-associated mutations, lead to drastic differences in critical temperature. These studies contribute to both qualitative and quantitative understanding on the phase behaviors of membraneless organelles and their regulation and dysregulation. |
Thursday, March 7, 2019 3:06PM - 3:42PM |
V51.00002: Identifying sequence-determinants of protein liquid-liquid phase separation using molecular simulations Invited Speaker: Jeetain Mittal In this talk, I will describe ongoing efforts in my group aimed at developing an accurate simulation model to study the liquid-like assemblies of disordered proteins. We use a "top-down" approach for constructing a Cα-based (one interaction site per amino acid) protein model, which involves comparisons with experimental data available from the recent literature as well as comparisons with atomistic single-chain simulations. The resulting model is found to be of enormous help in decoding the role of specific features of the protein sequence that control their liquid-liquid phase separation. We will demonstrate this with a combination of simulation and experiment data for several protein systems such as Laf-1, FUS, TDP-43. |
Thursday, March 7, 2019 3:42PM - 4:18PM |
V51.00003: Atomic details of protein/RNA liquid-liquid phase separation by experiment and simulation Invited Speaker: Nick Fawzi Phase separation of RNA-binding proteins via multivalent interactions between aromatic/polar-rich disordered domains contributes to the formation of functional cytoplasmic granules and nuclear puncta, which have been shown to behave as liquids -- flowing, fusing, and returning to spherical shape -- within live cells. These domains have also been identified as the nucleators of cytoplasmic inclusions associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We use atomic resolution nuclear magnetic resonance spectroscopy approaches to visualize low complexity domain structure and interactions along the pathway from monomer, to liquid-liquid phase separated state, to static aggregates and hydrogels. We show that the low complexity domains of RNA-binding protein Fused in Sarcoma (FUS LC, associated with ALS and FTD) and hnRNP A2 (associated with ALS and IBM) remain disordered even within liquid phase separated puncta (Burke et al. Molecular Cell, 2015). FUS LC also recruits unphosphorylated RNA-polymerase II C-terminal domain into the liquid phase separated state, adding a potential explanation for FUS LC transcriptional activation in cancer. Importantly, phase separation is reversible and is modulated by interaction with RNA, distinguishing these assemblies from static inclusions that can arise from missense mutations in the LC regions. In contrast, we show that liquid-liquid phase separation of TDP-43 is mediated in part by structured α-helical assembly and extension (Conicella et al. Structure, 2016). Some ALS-associated mutations disrupt helix-helix interaction inhibiting liquid-liquid phase separation while leading to enhanced aggregation. Our current work aims to evaluate the potential of post translational modification to alter assembly and hence disrupt pathological interactions of these disordered domains (Monahan and Ryan et al. EMBO J 2017). |
Thursday, March 7, 2019 4:18PM - 4:54PM |
V51.00004: Features and consequences for transcriptional activity of transcription factor condensation Invited Speaker: Xavier Salvatella Transcription activation relies on weak, transient interactions between the activation domains of transcription factors, general transcription factors, transcriptional co-regulators and RNA Pol II. Characterizing these interactions is important to understand the physical principles that govern this important process and, also, to identify opportunities for therapeutic intervention, especially in oncology. We are interested in characterizing how this type of interactions regulate the transcriptional activity of a specific transcription factor, the androgen receptor (AR) - the main therapeutic target for prostate cancer - and in perturbing them with small molecules. In this communication we will provide a characterization of the interactions established by the activation domain of AR [1–3] as well as evidence that the activation domain forms condensates [4] stabilized by hydrophobic interactions between partially structured motifs that are important for transcriptional activity. Finally we will put forward the hypothesis that the multivalent nature of these interactions is in part responsible for AR condensation at the initiation of transcription. |
Thursday, March 7, 2019 4:54PM - 5:30PM |
V51.00005: Observation of LLPS in Protein and Peptide solutions: Serendipitous or Ubiquitous? Invited Speaker: Ying Wang Liquid-liquid phase separation (LLPS) is a well-known phenomenon in the field of colloid physics. In the past few decades, LLPS has been reported for various protein solutions. Remarkably, LLPS of protein solutions was observed in living organisms, from “cold cataract” in the eye lenses of fish to the recently reported intracellular segregation of signal protein complexes. |
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