Xiaokun Shu, PhD

Professor

Department of Pharmaceutical Chemistry

[email protected]

555 Mission Bay Blvd South, Rm 452Y

UCSF Box 3122

San Francisco, CA 94158

United States

Links

Shu Lab UCSF Profiles

Affiliations

What I do

We apply laws of Physics and Chemistry to design tools for Biology, and use the novel tools to understand fascinating Biology and discover life-saving therapeutics.

Departmental research area

physical biology

chemical biology and medicinal chemistry

protein and cellular engineering

My research expertise

research ranges from structure-based reporter design to visualizing dynamic processes in living cells & animals, from protein engineering to drug discovery, from reading enzyme activities to manipulating protein functions & phase separation

Professional background

Biography

The Shu lab believes in what Richard Feynman said "If you're not having fun, you are not learning. There's a pleasure in finding things out." Thus, having fun is an essential part of our research life. Our students and postdoc trainees and the PI always find unexpected fun in their biological adventures because we are an interdisciplinary lab, focusing on visualizing inner life of living cells and animals. The cells' inner life is like a glowing beautiful world of Avatar, after we label many proteins in the cell with multicolor fluorescent reporters.

Our research interests span the fields of Physical Biology, Chemical Biology, Structural Biology, Protein Engineering, Cell & Molecular Biology, Developmental Biology, and Drug Discovery. We apply Physics, Chemistry and Engineering to design biological tools for visualizing and manipulating dynamic cell signaling in vivo in order to understand animal development and homeostasis, because dynamical features of signaling are the essence of living organisms. Effector proteins such as proteases and kinases regulate almost every major signaling pathways, and protein-protein interactions (PPIs) define specificity of signal transduction from extracellular cues to the appropriate intracellular effector proteins. We have developed new classes of fluorescent reporters of proteases, kinases, and PPIs. These reporters achieve large dynamic range, high brightness and fast kinetics, in addition being genetically encoded requiring no exogenous cofactor for non-invasive imaging. Our reporters enable robust and rapid imaging of dynamic signaling in living cells and animals with unexpected fun, identifying small molecules that inhibit dysregulated signaling in disease such as cancer. Other biological tools we are developing include: chemogenetic tools for manipulating protein interaction and liquid-liquid phase separation; a genetically encoded photosensitizer for activating caspase and apoptosis signaling and ablating single cells in live animals; singlet oxygen-mediated proximity labeling technologies for identifying weak and transient PPIs by mass spectrometry. We are applying these novel technologies to explore exciting biology and therapeutics. We also collaborate with many biologists and chemists. We have shared our tools by depositing them to not-for-profit organizations, e.g. Addgene, Bloomington Stock Center.

Together let's explore fascinating biology and discover life-saving therapeutics while having fun in the biological adventures!

Research keywords

Fluorescence Resonance Energy Transfer
Green Fluorescent Proteins
Protein Interaction Mapping
Peptide Hydrolases
Photosensitizing Agents
Genes, Reporter
Focal Adhesions
Protein Interaction Maps
Phosphotransferases
Ethacridine
Optical Imaging
Fluorescent Dyes
Singlet Oxygen
Ataxia Telangiectasia
Luminescent Proteins

1.	NIH Director's New Innovator Award, National Institute of Health, 2012

Publications

To TL, Li X, Shu X. Spying on SARS-CoV-2 with Fluorescent Tags and Protease Reporters. Viruses. 2023 09 27; 15(10).

Middha P, Wang X, Behrens S, Bolla MK, Wang Q, Dennis J, Michailidou K, Ahearn TU, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Auer PL, Augustinsson A, Baert T, Freeman LEB, Becher H, Beckmann MW, Benitez J, Bojesen SE, Brauch H, Brenner H, Brooks-Wilson A, Campa D, Canzian F, Carracedo A, Castelao JE, Chanock SJ, Chenevix-Trench G, CTS Consortium, Cordina-Duverger E, Couch FJ, Cox A, Cross SS, Czene K, Dossus L, Dugué PA, Eliassen AH, Eriksson M, Evans DG, Fasching PA, Figueroa JD, Fletcher O, Flyger H, Gabrielson M, Gago-Dominguez M, Giles GG, González-Neira A, Grassmann F, Grundy A, Guénel P, Haiman CA, Håkansson N, Hall P, Hamann U, Hankinson SE, Harkness EF, Holleczek B, Hoppe R, Hopper JL, Houlston RS, Howell A, Hunter DJ, Ingvar C, ABCTB Investigators, kConFab Investigators, Isaksson K, Jernström H, John EM, Jones ME, Kaaks R, Keeman R, Kitahara CM, Ko YD, Koutros S, Kurian AW, Lacey JV, Lambrechts D, Larson NL, Larsson S, Le Marchand L, Lejbkowicz F, Li S, Linet M, Lissowska J, Martinez ME, Maurer T, Mulligan AM, Mulot C, Murphy RA, Newman WG, Nielsen SF, Nordestgaard BG, Norman A, O'Brien KM, Olson JE, Patel AV, Prentice R, Rees-Punia E, Rennert G, Rhenius V, Ruddy KJ, Sandler DP, Scott CG, Shah M, Shu XO, Smeets A, Southey MC, Stone J, Tamimi RM, Taylor JA, Teras LR, Tomczyk K, Troester MA, Truong T, Vachon CM, Wang SS, Weinberg CR, Wildiers H, Willett W, Winham SJ, Wolk A, Yang XR, Zamora MP, Zheng W, Ziogas A, Dunning AM, Pharoah PDP, García-Closas M, Schmidt MK, Kraft P, Milne RL, Lindström S, Easton DF, Chang-Claude J. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry. Breast Cancer Res. 2023 08 09; 25(1):93.

Chung CI, Yang J, Shu X. Chemogenetic Minitool for Dissecting the Roles of Protein Phase Separation. ACS Cent Sci. 2023 Jul 26; 9(7):1466-1479.

Dekker J, Alber F, Aufmkolk S, Beliveau BJ, Bruneau BG, Belmont AS, Bintu L, Boettiger A, Calandrelli R, Disteche CM, Gilbert DM, Gregor T, Hansen AS, Huang B, Huangfu D, Kalhor R, Leslie CS, Li W, Li Y, Ma J, Noble WS, Park PJ, Phillips-Cremins JE, Pollard KS, Rafelski SM, Ren B, Ruan Y, Shav-Tal Y, Shen Y, Shendure J, Shu X, Strambio-De-Castillia C, Vertii A, Zhang H, Zhong S. Spatial and temporal organization of the genome: Current state and future aims of the 4D nucleome project. Mol Cell. 2023 08 03; 83(15):2624-2640.

Li X, Combs JD, Salaita K, Shu X. Polarized focal adhesion kinase activity within a focal adhesion during cell migration. Nat Chem Biol. 2023 Dec; 19(12):1458-1468.

Li X, Chung CI, Yang J, Chaudhuri S, Munster PN, Shu X. ATM-SPARK: A GFP phase separation-based activity reporter of ATM. Sci Adv. 2023 03; 9(9):eade3760.

Yang J, Xiao Y, Lidsky PV, Wu CT, Bonser LR, Peng S, Garcia-Knight MA, Tassetto M, Chung CI, Li X, Nakayama T, Lee IT, Nayak JV, Ghias K, Hargett KL, Shoichet BK, Erle DJ, Jackson PK, Andino R, Shu X. Fluorogenic reporter enables identification of compounds that inhibit SARS-CoV-2. Nat Microbiol. 2023 01; 8(1):121-134.

Lafaye C, Aumonier S, Torra J, Signor L, von Stetten D, Noirclerc-Savoye M, Shu X, Ruiz-González R, Gotthard G, Royant A, Nonell S. Riboflavin-binding proteins for singlet oxygen production. Photochem Photobiol Sci. 2022 Sep; 21(9):1545-1555.

Tsz-Leung To, Xiaokun Shu. Chapter 4 Major methods and technologies for assessing cell death. . 2022 Jan 1; 93-118.

Li X, Lidsky PV, Xiao Y, Wu CT, Garcia-Knight M, Yang J, Nakayama T, Nayak JV, Jackson PK, Andino R, Shu X. Ethacridine inhibits SARS-CoV-2 by inactivating viral particles. PLoS Pathog. 2021 09; 17(9):e1009898.

Li X, Lidsky P, Xiao Y, Wu CT, GarciaKnight M, Yang J, Nakayama T, Nayak JV, Jackson PK, Andino R, Shu X. Ethacridine inhibits SARS-CoV-2 by inactivating viral particles in cellular models. bioRxiv. 2020 Nov 02.

Guo WH, Qi X, Yu X, Liu Y, Chung CI, Bai F, Lin X, Lu D, Wang L, Chen J, Su LH, Nomie KJ, Li F, Wang MC, Shu X, Onuchic JN, Woyach JA, Wang ML, Wang J. Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry. Nat Commun. 2020 08 26; 11(1):4268.

Shu X. Imaging dynamic cell signaling in vivo with new classes of fluorescent reporters. Curr Opin Chem Biol. 2020 02; 54:1-9.

Zhang Q, Schepis A, Huang H, Yang J, Ma W, Torra J, Zhang SQ, Yang L, Wu H, Nonell S, Dong Z, Kornberg TB, Coughlin SR, Shu X. Designing a Green Fluorogenic Protease Reporter by Flipping a Beta Strand of GFP for Imaging Apoptosis in Animals. J Am Chem Soc. 2019 03 20; 141(11):4526-4530.

Torra J, Lafaye C, Signor L, Aumonier S, Flors C, Shu X, Nonell S, Gotthard G, Royant A. Tailing miniSOG: structural bases of the complex photophysics of a flavin-binding singlet oxygen photosensitizing protein. Sci Rep. 2019 02 20; 9(1):2428.

Chung CI, Zhang Q, Shu X. Dynamic Imaging of Small Molecule Induced Protein-Protein Interactions in Living Cells with a Fluorophore Phase Transition Based Approach. Anal Chem. 2018 12 18; 90(24):14287-14293.

Zhang SQ, Huang H, Yang J, Kratochvil HT, Lolicato M, Liu Y, Shu X, Liu L, DeGrado WF. Designed peptides that assemble into cross-α amyloid-like structures. Nat Chem Biol. 2018 09; 14(9):870-875.

Zhang Q, Zheng YW, Coughlin SR, Shu X. A rapid fluorogenic GPCR-β-arrestin interaction assay. Protein Sci. 2018 04; 27(4):874-879.

Shao-Qing Zhang, Lijun Liu, Junjiao Yang, Marco Lolicato, Huong Kratochvil, Xiaokun Shu, William F. DeGrado. De Novo Design of Cross-a Amyloid-Like Fibrils with Cellular Activity. Biophysical Journal. 2018 Feb 1; 114(3):410a.

Zhang Q, Huang H, Zhang L, Wu R, Chung CI, Zhang SQ, Torra J, Schepis A, Coughlin SR, Kornberg TB, Shu X. Visualizing Dynamics of Cell Signaling In Vivo with a Phase Separation-Based Kinase Reporter. Mol Cell. 2018 01 18; 69(2):347.

To TL, Shu X. Detecting Activity at Different Length Scales: From Subdiffraction to Whole-Animal Activity. Biochemistry. 2017 10 03; 56(39):5163-5164.

Makhijani K, To TL, Ruiz-González R, Lafaye C, Royant A, Shu X. Precision Optogenetic Tool for Selective Single- and Multiple-Cell Ablation in a Live Animal Model System. Cell Chem Biol. 2017 Jan 19; 24(1):110-119.

Rodriguez EA, Campbell RE, Lin JY, Lin MZ, Miyawaki A, Palmer AE, Shu X, Zhang J, Tsien RY. The Growing and Glowing Toolbox of Fluorescent and Photoactive Proteins. Trends Biochem Sci. 2017 02; 42(2):111-129.

Erik A Rodriguez, Geraldine N Tran, Larry A Gross, Jessica L Crisp, Xiaokun Shu, John Y Lin, Roger Y Tsien. Erratum: Corrigendum: A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein. Nature Methods. 2016 Oct 1; 13(10):890-890.

Rodriguez EA, Tran GN, Gross LA, Crisp JL, Shu X, Lin JY, Tsien RY. A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein. Nat Methods. 2016 09; 13(9):763-9.

Feliks M, Lafaye C, Shu X, Royant A, Field M. Structural Determinants of Improved Fluorescence in a Family of Bacteriophytochrome-Based Infrared Fluorescent Proteins: Insights from Continuum Electrostatic Calculations and Molecular Dynamics Simulations. Biochemistry. 2016 08 09; 55(31):4263-74.

To TL, Schepis A, Ruiz-González R, Zhang Q, Yu D, Dong Z, Coughlin SR, Shu X. Rational Design of a GFP-Based Fluorogenic Caspase Reporter for Imaging Apoptosis In Vivo. Cell Chem Biol. 2016 07 21; 23(7):875-882.

To TL, Medzihradszky KF, Burlingame AL, DeGrado WF, Jo H, Shu X. Photoactivatable protein labeling by singlet oxygen mediated reactions. Bioorg Med Chem Lett. 2016 07 15; 26(14):3359-3363.

To TL, Zhang Q, Shu X. Structure-guided design of a reversible fluorogenic reporter of protein-protein interactions. Protein Sci. 2016 Mar; 25(3):748-53.

Yu D, Dong Z, Gustafson WC, Ruiz-González R, Signor L, Marzocca F, Borel F, Klassen MP, Makhijani K, Royant A, Jan YN, Weiss WA, Guo S, Shu X. Rational design of a monomeric and photostable far-red fluorescent protein for fluorescence imaging in vivo. Protein Sci. 2016 Feb; 25(2):308-15.

Yu D, Baird MA, Allen JR, Howe ES, Klassen MP, Reade A, Makhijani K, Song Y, Liu S, Murthy Z, Zhang SQ, Weiner OD, Kornberg TB, Jan YN, Davidson MW, Shu X. A naturally monomeric infrared fluorescent protein for protein labeling in vivo. Nat Methods. 2015 Aug; 12(8):763-5.

To TL, Piggott BJ, Makhijani K, Yu D, Jan YN, Shu X. Rationally designed fluorogenic protease reporter visualizes spatiotemporal dynamics of apoptosis in vivo. Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11):3338-43.

To TL, Fadul MJ, Shu X. Singlet oxygen triplet energy transfer-based imaging technology for mapping protein-protein proximity in intact cells. Nat Commun. 2014 Jun 06; 5:4072.

Yu D, Gustafson WC, Han C, Lafaye C, Noirclerc-Savoye M, Ge WP, Thayer DA, Huang H, Kornberg TB, Royant A, Jan LY, Jan YN, Weiss WA, Shu X. An improved monomeric infrared fluorescent protein for neuronal and tumour brain imaging. Nat Commun. 2014 May 15; 5:3626.

Asensio CS, Sirkis DW, Maas JW, Egami K, To TL, Brodsky FM, Shu X, Cheng Y, Edwards RH. Self-assembly of VPS41 promotes sorting required for biogenesis of the regulated secretory pathway. Dev Cell. 2013 Nov 25; 27(4):425-37.

Tsz-Leung To, Xiaokun Shu. Singlet Oxygen Triplet Energy Transfer (STET) Based Imaging Technologies for Mapping Protein-Protein Proximity and Interactions in Intact Cells. Biophysical Journal. 2013 Jan 1; 104(2):501a.

Butko MT, Yang J, Geng Y, Kim HJ, Jeon NL, Shu X, Mackey MR, Ellisman MH, Tsien RY, Lin MZ. Fluorescent and photo-oxidizing TimeSTAMP tags track protein fates in light and electron microscopy. Nat Neurosci. 2012 Dec; 15(12):1742-51.

Ou HD, Kwiatkowski W, Deerinck TJ, Noske A, Blain KY, Land HS, Soria C, Powers CJ, May AP, Shu X, Tsien RY, Fitzpatrick JA, Long JA, Ellisman MH, Choe S, O'Shea CC. A structural basis for the assembly and functions of a viral polymer that inactivates multiple tumor suppressors. Cell. 2012 Oct 12; 151(2):304-19.

T.J. Deerinck, E. Bushong, R. Tsien, M. Ellisman, X. Shu. Advances in Correlated Light and Electron Microscopy Imaging Probes. Microscopy and Microanalysis. 2012 Jul 1; 18(S2):834-835.

Qi YB, Garren EJ, Shu X, Tsien RY, Jin Y. Photo-inducible cell ablation in Caenorhabditis elegans using the genetically encoded singlet oxygen generating protein miniSOG. Proc Natl Acad Sci U S A. 2012 May 08; 109(19):7499-504.

Ellisman MH, Deerinck TJ, Shu X, Sosinsky GE. Picking faces out of a crowd: genetic labels for identification of proteins in correlated light and electron microscopy imaging. Methods Cell Biol. 2012; 111:139-55.

M Ellisman, X Shu, V Lev-Ram, T Deerinck, R Tsien, S Lamont, J Martinez, M Berlanga, E Bushong, M Martone, S Larson. Bridging Gaps in Imaging by Applying EM Tomography and Serial Block Face SEM, Including a New Genetically Encoded Tag for Correlated Light and 3D Electron Microscopy of Intact Cells, Tissues and Organisms: Integrating the Resulting Correlated Image Data Using the Whole Brain Catalog. Microscopy and Microanalysis. 2011 Jul 1; 17(S2):2-3.

Shu X, Lev-Ram V, Deerinck TJ, Qi Y, Ramko EB, Davidson MW, Jin Y, Ellisman MH, Tsien RY. A genetically encoded tag for correlated light and electron microscopy of intact cells, tissues, and organisms. PLoS Biol. 2011 Apr; 9(4):e1001041.

TJ Deerinck, EA Bushong, V Lev-Ram, X Shu, RY Tsien, MH Ellisman. Enhancing Serial Block-Face Scanning Electron Microscopy to Enable High Resolution 3-D Nanohistology of Cells and Tissues. Microscopy and Microanalysis. 2010 Jul 1; 16(S2):1138-1139.

Xiaokun Shu, Varda Lev-Ram, Guido M. Gaietta, Thomas J. Deerinck, Ericka B. Ramko, Michael W. Davidson, Mark H. Ellisman, Roger Y. Tsien. Genetically Encoded Singlet Oxygen Generator (SOG) Requiring No Exogenous Cofactors. Biophysical Journal. 2010 Jan 1; 98(3):612a.

Shu X, Royant A, Lin MZ, Aguilera TA, Lev-Ram V, Steinbach PA, Tsien RY. Mammalian expression of infrared fluorescent proteins engineered from a bacterial phytochrome. Science. 2009 May 08; 324(5928):804-7.

Shu X, Wang L, Colip L, Kallio K, Remington SJ. Unique interactions between the chromophore and glutamate 16 lead to far-red emission in a red fluorescent protein. Protein Sci. 2009 Feb; 18(2):460-6.

Shu X, Leiderman P, Gepshtein R, Smith NR, Kallio K, Huppert D, Remington SJ. An alternative excited-state proton transfer pathway in green fluorescent protein variant S205V. Protein Sci. 2007 Dec; 16(12):2703-10.

Shu X, Kallio K, Shi X, Abbyad P, Kanchanawong P, Childs W, Boxer SG, Remington SJ. Ultrafast excited-state dynamics in the green fluorescent protein variant S65T/H148D. 1. Mutagenesis and structural studies. Biochemistry. 2007 Oct 30; 46(43):12005-13.

Shi X, Abbyad P, Shu X, Kallio K, Kanchanawong P, Childs W, Remington SJ, Boxer SG. Ultrafast excited-state dynamics in the green fluorescent protein variant S65T/H148D. 2. Unusual photophysical properties. Biochemistry. 2007 Oct 30; 46(43):12014-25.

Leiderman P, Genosar L, Huppert D, Shu X, Remington SJ, Solntsev KM, Tolbert LM. Ultrafast excited-state dynamics in the green fluorescent protein variant S65T/H148D. 3. Short- and long-time dynamics of the excited-state proton transfer. Biochemistry. 2007 Oct 30; 46(43):12026-36.

Shu X, Shaner NC, Yarbrough CA, Tsien RY, Remington SJ. Novel chromophores and buried charges control color in mFruits. Biochemistry. 2006 Aug 15; 45(32):9639-47.

Quillin ML, Anstrom DM, Shu X, O'Leary S, Kallio K, Chudakov DM, Remington SJ. Kindling fluorescent protein from Anemonia sulcata: dark-state structure at 1.38 A resolution. Biochemistry. 2005 Apr 19; 44(15):5774-87.

X.K.Shu, P. Jiang, J.G. Che. Surface alloying of immiscible metals induced by surface state shift. Surface Science. 2003; 545(3):199-210.