經歷

學歷

榮譽

指導學生獲獎

研究方向

在一顆細胞內，有成千上萬的生物化學反應同時在發生著。然而，這些參與反應的生物分子，如蛋白質、核酸等，它們怎麼「知道」自己該在何時、何處參與那些反應？這是我們實驗室最有興趣了解的問題。
真核細胞內有一半以上的蛋白質帶有無特定三維結構的「固有無序」區段(intrinsically disordered domains; IDPs or IDRs)，這些無序區段的特性，很可能就決定了該蛋白質該在何時何處參與反應。近來有些研究已發現許多這類蛋白質可以利用外界環境(如酸鹼度、溫度)的改變(「何時」)進行液-液相分離(liquid-liquid phase separation; LLPS)，藉以達到在細胞內局部的濃度提高，而在特定地點發生反應(「何處」)。除了多種功能外，這些區段的變異也和多種疾病有關，而我們實驗室有興趣的主題皆是為了解IDP/LLPS的特性及其生物功能與疾病間的關係。目前著重的主題可分為下列幾項：

1. 基因調控 : 我們目前研究多個帶有IDR的RNA binding proteins和transcription factors。我們希望了解這些IDR是如何調控它們相關的基因及功能的。
2. 神經退化性疾病 : TDP-43 這個蛋白質無序區段的不正常堆集是漸凍人症和一種失智症的主要原因。這個無序區段是怎麼堆集的？為什麼自然要演化出會不正常堆集的區段？這個區段是不是還有其它功能？這是我們有興趣的問題。
3. 癌症 : Galectin-3 是人體內唯一一種帶有無序區段的半乳糖凝集素。它在發炎及一些癌細胞內會大量產生，但它產生的機制和癌症之間的關係並不清楚，這也是我們目前研究的方向之一。
4. 藥物設計 : 現在以蛋白質結構為基礎的藥物開發(structure-based drug design)都是以有三級結構的活性位或調節位做設計，鮮少以無序區段作為目標。以上(1)-(3)提到的功能與疾病，我們發現都和IDR所調控的LLPS有關。因此，我們會針對會形成液-液相分離的無序蛋白質為目標，針對它們凝集作用的機制，來找出適合調控這些機制的藥物。
5. 人工智慧和生物資訊學：我們利用資料庫中的同源IDR來訓練模型，讓AI去找出IDR中可能功能很重要的胺基酸。我們也分析多種蛋白質序列資料庫，希望了解IDR是如何演化出來的。

研究著作

Lin PH, Wu GW, Lin YH, Huang JR, Jeng US, Liu WM*, and Huang JR*  TDP-43 amyloid fibril formation via phase separation-related and -unrelated pathways (2024) ACS Chem Neurosci.

Sun YC, Hsieh TL, Lin CY, Shao WY, Lin YH,and Huang JR*. A few charged residues in galectin-3’s folded and disordered regions regulate phase separation (2024) Adv Sci 2402570.

Siew JJ, Chen HM, Chiu FL, Lee CW, Chang YM, Chen HL, Nguyen TNA, Liao HT, Liu M, Hagar HT, Sun YC, Lai HL, Kuo MH, Blum D, Buee L, Jin LW, Chen SY, Ko TM, Huang JR, Kuo HC, Liu FT, and Chern Y. Galectin-3 aggravates microglial activation and tau transmission in tauopathy (2023) J Clin Invest 134(2):e165523.

Ho WL, Huang HC, and Huang JR*. IFF: Identifying key residues in intrinsically disordered regions of proteins using machine learning (2023) Prot Sci 3;32:e4739 

Chou MC, Wang YH, Chen FY, Kung CY, Wu KP, Kuo JC, Chan SJ, Cheng ML, Lin CY, Chou YC, Ho MC, Firestine S, Jie-rong Huang, Chen RH. PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly (2023) Mol Cell 

Chiu SH, Ho WL, Sun YC, Kuo JC, and Huang JR*. Phase separation driven by interchangeable properties in the intrinsically disordered regions of protein paralogs. (2022) Comm. Biol. 5:400

Ho WL and Huang JR*. The return of the rings: Evolutionary convergence of aromatic residues in the intrinsically disordered regions of RNA-binding proteins for liquid-liquid phase separation. (2022) Prot Sci 31:e4317

Chiang WC, Lee MH, Chen TC, and Huang JR*. Interactions between the Intrinsically Disordered Regions of hnRNP-A2 and TDP-43 Accelerate TDP-43′s Conformational Transition. (2020) Int J Mol Sci. 21(16), 5930

Chiu YP, Sun YC, Qiu DC, Lin YH, Chen YQ, Kuo JC, and Huang JR*. Liquid-liquid phase separation and extracellular multivalent interactions in the tale of galectin-3. (2020) Nat Comm 11:1229

Chen TC and Huang JR*. Musashi-1: An Example of How Polyalanine Tracts Contribute to Self-Association in the Intrinsically Disordered Regions of RNA-Binding Proteins. (2020) Int J Mol Sci. 21(7). pii: E2289

Li HR, Chiang WC, Chou PC, Wang WJ, Huang JR*. TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase separation is mediated by just a few aromatic residues. (2018) J Biol Chem. 293(16):6090-6098

Li HR, Chen TC, Hsiao CL, Shi L, Chou CY, Huang JR*. The physical forces mediating self-association and phase-separation in the C-terminal domain of TDP-43. (2018) BBA-Proteins and Proteomics. 1866:214-223

Lin YH, Qiu DC, Chang WH, Yeh YQ, Jeng US, Liu FT, Huang JR*. The intrinsically disordered N-terminal domain of galectin-3 dynamically mediates multisite self-association of the protein through fuzzy interactions. (2017) J Biol Chem. 292(43) 17845–17856

Chen TC, Hsiao CL, Huang SJ, Huang JR*. The nearest-neighbor effect on random-coil NMR chemical shifts demonstrated using a low-complexity amino-acid sequence. (2016) Protein Pept Lett. 23(11):967-975

Delaforge E, Milles S, Huang JR, Bouvier D, Jensen MR, Sattler M, Hart JD, Blackledge M. Investigating the Role of Large-Scale Domain Dynamics in Protein-Protein Interactions. (2016) Front. Mol. Biosci. 3:54

Aznauryan M, Delgado L, Soranno A, Nettels D, Huang JR, Labhardt AM, Grzesiek S, Schuler B. Comprehensive structural and dynamical view of an unfolded protein from the combination of single-molecule FRET, NMR, and SAXS. (2016) PNAS. 113(37):E5389-98

Huang JR, Warner LR, Sanchez C, Gabel F, Madl T, Mackereth CD, Sattler M, Blackledge M. Transient electrostatic interactions dominate the conformational equilibrium sampled by multi-domain splicing factor U2AF65: A combined NMR and SAXS study. (2014) J Am Chem Soc. 136(19):7068-76

Jensen MR, Zweckstetter M, Huang JR, Blackledge M. Exploring Free-Energy Landscapes of Intrinsically Disordered Proteins at Atomic Resolution Using NMR Spectroscopy. (2014) Chem Rev. 114(13):6632-60
Before 2013

Huang J-R, Ozenne V, Jensen MR, and Blackledge M. Direct prediction of NMR residual dipolar couplings from the primary sequence of unfolded proteins. (2013) Angew Chem Int Ed. 52(2):687-690 (Cover Issue)

Huang J-R, Gentner M, Vajpai N, Grzesiek S, and Blackledge M. Residual dipolar couplings measured in unfolded proteins are sensitive to amino- acid specific geometries as well as local conformational sampling. (2012) Biochem Soc T. 40(5):989-94

Ozenne V, Schneider R, Yao M, Huang J-R, Salmon L, Zweckstetter M, Jensen MR and Blackledge M. Mapping the potential energy landscape of intrinsically disordered proteins at amino acid resolution. (2012) J Am Chem Soc. 134(36):15138-48

Ozenne V, Bauer F, Salmon L, Huang J-R, Jensen MR, Segard S, Bernado P, Charavay C, and Blackledge M. Flexible-meccano: A tool for the generation of explicit ensemble description of intrinsically dis- ordered proteins and their associated experimental observables. (2012) Bioinfomatics. 28(11):1463-70

Silvers R, Sziegat F, Tachibana H, Segawa S, Whittaker S, Gunther U, Gabel F, Huang J-R, Blackledge M, Wirmer J, and Schwalbe H. Modulation of structure and dynamics by disulfide bond formation in unfolded states. (2012) J Am Chem Soc. 134(15):6846-54

Huang J-R, Gabel F, Jensen MR, Grzesiek S, and Blackledge M. Sequencespecific mapping of the interaction between urea and unfolded ubiquitin from ensemble analysis of NMR and small angle scattering data. (2012) J Am Chem Soc. 134(9):4429-36

Schneider R, Huang J-R, Yao M, Communie G, Ozenne V, Mollica L, Salmon L, Jensen MR, and Blackledge M. Towards a robust descrip- tion of intrinsic protein disorder using nuclear magnetic resonance spec- troscopy. (2012) Mol Biosyst. 8(1):58-68

Vajpai N, Gentner M, Huang J-R, Blackledge M, and Grzesiek S. Sidechain χ1 conformations in urea-denatured ubiquitin and protein G from 3J coupling constants and residual dipolar couplings. (2010) J Am Chem Soc. 132(9):3196-203

Huang J-R and Grzesiek S. Ensemble calculations of unstructured proteins constrained by RDC and PRE data: a case study of urea-denatured ubiquitin. (2010) J Am Chem Soc. 132(2):694-705

Haussinger D, Huang J-R, and Grzesiek S. DOTA-M8–an extremely rigid, high-affinity lanthanide chelating tag for PCS NMR. (2009) J Am Chem Soc. 131(41):14761-7

Huang J-R, Hsu S-TD, Christodoulou J, and Jackson SE. The extremely slow-exchanging core and acid-denatured state of Green Fluorescent Pro- tein. (2008) HFSP Journal. 2(6):378-87

Huang J-R, Craggs TD, Christodoulou J, and Jackson SE. Stable intermediate states and high energy barriers in the unfolding of GFP. (2007) J Mol Biol. 370(2):356-71

Jackson SE, Craggs TD, Huang J-R. Understanding the folding of GFP using biophysical techniques. (2006) Expert Rev Proteomics. 3(5):545-59