Mini-symposium on Disordered Proteins
— from functional assembly to disease aggregation
蛋白質結構可用人工智慧的工具預測且已經取得了令人矚目的成就，並獲得了2024年諾貝爾化學獎的肯定。然而，這個故事還沒有結束。機器學習在蛋白質結構預測方面仍面臨諸多挑戰，其中之一就是結構預測工具無法應用於沒有結構或帶有無結構區段的無序蛋白 (Intrinsically disordered proteins, IDPs, or proteins with intrinsically disordered regions, IDRs)。
自然界中，有一半以上的蛋白質是無序蛋白或含有無序區段，並且越來越多的研究顯示它們在多種生理功能中扮演重要角色。其中最受矚目的一個研究方向是，許多無序蛋白能夠透過液-液相分離 (Liquid-Liquid Phase Separation, LLPS) 形成所謂的無膜胞器，從而在細胞內特定的時間和地點精確地執行其功能。然而，這類功能性聚集 (Functional Assembly) 有時也伴隨著代價，例如形成與神經退化性疾病相關的有害聚集體 (Disease Aggregation)。
本次 Mini-Symposium 聚焦於 Disordered Proteins 的研究，邀請了四位國內外頂尖專家，來探討無序蛋白在功能調控及疾病發生中的角色。
講者介紹
Tanja Mittag 博士的研究專注於相分離現象及其在細胞生物學中的應用，尤其是與神經退化性疾病之間的關係。她近年以通訊作者身份在 Science、Cell、Nature Cell Biology、Molecular Cell 等頂尖期刊上發表了多篇重要研究。Pau Bernadó 博士則是結構生物學領域的專家，擅長利用同步輻射光源、核磁共振光譜學等技術來研究無序蛋白（特別是 homopeptide-repeat 蛋白）的動態與聚集行為，其實驗室也持續在 Nature Structural & Molecular Biology、JACS、Angewandte Chemie、Structure 等頂尖期刊上發表相關研究。
台灣的兩位專家亦備受矚目。中央研究院基因體中心的副所長陳韻如博士是國內研究神經退化疾病的傑出專家，從蛋白質的角度深入探討疾病機制，並發表了多項傑出成果且獲得了許多獎項肯定。陽明交通大學的朱智瑋博士則是知名的計算生物學專家，專注於開發計算方法模擬生物系統，揭示生物功能的形成機制。近年來，他亦與本校楊進木院長及蕭育源博士合作，致力於設計針對 IDP 的藥物。
更詳細的介紹請參考以下連結(Speakers' webpage)：
演講時刻表 Schedule
- Tanja Mittag : Understanding the driving forces for phase separation, the material properties of condensates, and their aging processes related to neurodegenerative diseases
- Pau Bernadó : A Structural Perspective of the Pathological Threshold in Huntington’s Disease
- Break
- Yun-Ru (Ruby) Chen : Understanding aggregation of TDP-43 and dipeptide repeats in neurodegenerative diseases and developing therapeutic potentials
- Jhih-Wei Chu : Physics-Based Machine Learning for Understanding Heterogeneous Rigidity in Protein Dynamics
- Discussion
Selected publications from Tanja Mittag's lab
- Farag M, Borcherds WM, Bremer A, Mittag T*, Pappu RV*. Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions. Nat Commun;14(1):5527, 2023.
- Cuneo MJ, O'Flynn BG, Lo, Y-H, Sabri N, Mittag T*. Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation. Mol Cell, 2023.
- Bremer A, Farag M, Borcherds WM, Peran I, Martin EW, Pappu RV*, Mittag T*. Deciphering how naturally occurring sequence features impact the phase behaviors of disordered prion-like domains. Nat Chemistry 13: 196-207, 2022.
- Martin EW, Harmon TS, Hopkins JB, Chakravarthy S, Incicco J, Schuck P, Soranno A, Mittag T*. A multi-step nucleation process determines the kinetics of prion-like domain phase separation. Nat Commun. 12(1):4513, 2021.
- Martin EW, Thomasen FE, Milkovic NM, Cuneo MJ, Grace CR, Nourse A, Lindorff-Larsen K, Mittag T*. Interplay of folded domains and the disordered low-complexity domain in mediating hnRNPA1 phase separation. Nucleic Acids Res 49(5): 2931-2945, 2021.
- Martin EW, Holehouse AS, Peran I, Farag M, Incicco JJ, Bremer A, Grace CR, Soranno A, Pappu RV*, Mittag T*. Valence and patterning of aromatic residues determine the phase behavior of disordered prion-like domains. Science 367(6478):694-699, 2020.
- Schmit JD, Bouchard JJ, Martin EW, Mittag T*. Protein network structure enables switching between liquid and gel states. JACS 142(2):874-883, 2020.
- Bouchard JJ, Otero JH, Scott DC, Szulc EM, Martin EW, Sabri N, Granata D, Marzahn MR, Lindorff-Larsen K, Salvatella X, Schulman BA, Mittag T*. Cancer mutations of the tumor suppressor SPOP disrupt the formation of active, phase-separated compartments. Mol Cell 72:19-36, 2018.
- Martin EW, Holehouse A, Grace CR, Hughes A, Pappu RV, Mittag T*. Sequence determinants of the conformational properties of an intrinsically disordered protein prior to and upon multisite phosphorylation. JACS 138(47):15323-15335, 2016.
- Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T*, Taylor JP*. Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization. Cell 163(1): 123-33, 2015.
Selected publications from Pau Bernadó's lab
- Elena-Real CA, Mier P, Sibille N, Andrade-Navarro MA, Bernadó P*. Structure-function relationships in protein homorepeats. Curr Opin Struct Biol. 2023.
- Elena-Real CA, Urbanek A, Imbert L, Morató A, Fournet A, Allemand F, Sibille N, Boisbouvier J, Bernadó P*. Site-Specific Introduction of Alanines for the Nuclear Magnetic Resonance Investigation of Low-Complexity Regions and Large Biomolecular Assemblies. ACS Chem Biol. 2023.
- Elena-Real CA, Urbanek A, Lund XL, Morató A, Sagar A, Fournet A, Estaña A, Bellande T, Allemand F, Cortés J, Sibille N, Melki R, Bernadó P*. Multi-site-specific isotopic labeling accelerates high-resolution structural investigations of pathogenic huntingtin exon-1. Structure. 2023.
- Elena-Real CA, Sagar A, Urbanek A, Popovic M, Morató A, Estaña A, Fournet A, Doucet C, Lund XL, Shi ZD, Costa L, Thureau A, Allemand F, Swenson RE, Milhiet PE, Crehuet R, Barducci A, Cortés J, Sinnaeve D, Sibille N, Bernadó P*. The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity. Nat Struct Mol Biol. 2022.
- Sagar A, Herranz-Trillo F, Langkilde AE, Vestergaard B, Bernadó P*. Structure and thermodynamics of transient protein-protein complexes by chemometric decomposition of SAXS datasets. Structure. 2021.
- Sagar A, Svergun D, Bernadó P*. Structural Analyses of Intrinsically Disordered Proteins by Small-Angle X-Ray Scattering. Methods Mol Biol. 2020.
- Urbanek A, Popovic M, Morató A, Estaña A, Elena-Real CA, Mier P, Fournet A, Allemand F, Delbecq S, Andrade-Navarro MA, Cortés J, Sibille N, Bernadó P*. Flanking Regions Determine the Structure of the Poly-Glutamine in Huntingtin through Mechanisms Common among Glutamine-Rich Human Proteins. Structure. 2020.
- Urbanek A, Popovic M, Elena-Real CA, Morató A, Estaña A, Fournet A, Allemand F, Gil AM, Cativiela C, Cortés J, Jiménez AI, Sibille N, Bernadó P*. Evidence of the Reduced Abundance of Proline cis Conformation in Protein Poly Proline Tracts. J Am Chem Soc. 2020.
- Cordeiro TN, Sibille N, Germain P, Barthe P, Boulahtouf A, Allemand F, Bailly R, Vivat V, Ebel C, Barducci A, Bourguet W, le Maire A, Bernadó P*. Interplay of Protein Disorder in Retinoic Acid Receptor Heterodimer and Its Corepressor Regulates Gene Expression. Structure. 2019.
- Estaña A, Sibille N, Delaforge E, Vaisset M, Cortés J, Bernadó P*. Realistic Ensemble Models of Intrinsically Disordered Proteins Using a Structure-Encoding Coil Database. Structure. 2019.
- Urbanek A, Morató A, Allemand F, Delaforge E, Fournet A, Popovic M, Delbecq S, Sibille N, Bernadó P*. A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats. Angew Chem Int Ed Engl. 2018.
- Cordeiro TN, Herranz-Trillo F, Urbanek A, Estaña A, Cortés J, Sibille N, Bernadó P*. Structural Characterization of Highly Flexible Proteins by Small-Angle Scattering. Adv Exp Med Biol. 2017.
- Cordeiro TN, Chen PC, De Biasio A, Sibille N, Blanco FJ, Hub JS, Crehuet R, Bernadó P*. Disentangling polydispersity in the PCNA-p15PAF complex, a disordered, transient and multivalent macromolecular assembly. Nucleic Acids Res. 2017.
- Herranz-Trillo F, Groenning M, van Maarschalkerweerd A, Tauler R, Vestergaard B, Bernadó P*. Structural Analysis of Multi-component Amyloid Systems by Chemometric SAXS Data Decomposition. Structure. 2017.
- Cordeiro TN, Herranz-Trillo F, Urbanek A, Estaña A, Cortés J, Sibille N, Bernadó P*. Small-angle scattering studies of intrinsically disordered proteins and their complexes. Curr Opin Struct Biol. 2017.