In-solution structure and oligomerization of human histone deacetylase 6 - an integrative approach
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
36062318
DOI
10.1111/febs.16616
Knihovny.cz E-resources
- Keywords
- acetylation, analytical ultracentrifugation, intrinsically disordered regions, oligomerization, small-angle X-ray scattering,
- MeSH
- Acetylation MeSH
- Histone Deacetylase 6 genetics chemistry metabolism MeSH
- Histone Deacetylases * metabolism MeSH
- Histone Deacetylase Inhibitors MeSH
- Humans MeSH
- Microtubules * metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Histone Deacetylase 6 MeSH
- Histone Deacetylases * MeSH
- Histone Deacetylase Inhibitors MeSH
Human histone deacetylase 6 (HDAC6) is a structurally unique, multidomain protein implicated in a variety of physiological processes including cytoskeletal remodelling and the maintenance of cellular homeostasis. Our current understanding of the HDAC6 structure is limited to isolated domains, and a holistic picture of the full-length protein structure, including possible domain interactions, is missing. Here, we used an integrative structural biology approach to build a solution model of HDAC6 by combining experimental data from several orthogonal biophysical techniques complemented by molecular modelling. We show that HDAC6 is best described as a mosaic of folded and intrinsically disordered domains that in-solution adopts an ensemble of conformations without any stable interactions between structured domains. Furthermore, HDAC6 forms dimers/higher oligomers in a concentration-dependent manner, and its oligomerization is mediated via the positively charged N-terminal microtubule-binding domain. Our findings provide the first insights into the structure of full-length human HDAC6 and can be used as a basis for further research into structure function and physiological studies of this unique deacetylase.
Centre for Structural Systems Biology Deutsches Elektronen Synchrotron Hamburg Germany
Department of Health Sciences and Biomedicine School of Life Sciences University of Siegen Germany
Department of Physical Chemistry Faculty of Natural Science Charles University Prague Czech Republic
European Molecular Biology Laboratory Hamburg Outstation c o DESY Germany
European XFEL GmbH Schenefeld Germany
Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Vestec Czech Republic
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Marmorstein R, Roth SY. Histone acetyltransferases: function, structure, and catalysis. Curr Opin Genet Dev. 2001;11(2):155-61.
Gray SG, Ekstrom TJ. The human histone deacetylase family. Exp Cell Res. 2001;262(2):75-83.
Grozinger CM, Hassig CA, Schreiber SL. Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc Natl Acad Sci USA. 1999;96(9):4868-73.
Miyake Y, Keusch JJ, Wang L, Saito M, Hess D, Wang X, et al. Structural insights into HDAC6 tubulin deacetylation and its selective inhibition. Nat Chem Biol. 2016;12(9):748-54.
Hai Y, Christianson DW. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat Chem Biol. 2016;12(9):741-7.
Shen S, Picci C, Ustinova K, Benoy V, Kutil Z, Zhang G, et al. Tetrahydroquinoline-capped histone deacetylase 6 inhibitor SW-101 ameliorates pathological phenotypes in a Charcot-Marie-tooth type 2A mouse model. J Med Chem. 2021;64(8):4810-40.
Porter NJ, Mahendran A, Breslow R, Christianson DW. Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors. Proc Natl Acad Sci USA. 2017;114(51):13459-64.
Shen S, Hadley M, Ustinova K, Pavlicek J, Knox T, Noonepalle S, et al. Discovery of a new isoxazole-3-hydroxamate-based histone deacetylase 6 inhibitor SS-208 with antitumor activity in syngeneic melanoma mouse models. J Med Chem. 2019;62(18):8557-77.
Bhatia S, Krieger V, Groll M, Osko JD, Reßing N, Ahlert H, et al. Discovery of the first-in-class dual histone deacetylase-proteasome inhibitor. J Med Chem. 2018;61(22):10299-309.
Zou H, Wu Y, Navre M, Sang BC. Characterization of the two catalytic domains in histone deacetylase 6. Biochem Biophys Res Commun. 2006;341(1):45-50.
Skultetyova L, Ustinova K, Kutil Z, Novakova Z, Pavlicek J, Mikesova J, et al. Human histone deacetylase 6 shows strong preference for tubulin dimers over assembled microtubules. Sci Rep. 2017;7(1):11547.
Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417(6887):455-8.
Kovacs JJ, Murphy PJM, Gaillard S, Zhao X, Wu JT, Nicchitta CV, et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell. 2005;18(5):601-7.
Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem. 2005;280(29):26729-34.
Saito M, Hess D, Eglinger J, Fritsch AW, Kreysing M, Weinert BT, et al. Acetylation of intrinsically disordered regions regulates phase separation. Nat Chem Biol. 2019;15(1):51-61.
Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 2003;115(6):727-38.
Verdel A, Curtet S, Brocard MP, Rousseaux S, Lemercier C, Yoshida M, et al. Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm. Curr Biol. 2000;10(12):747-9.
Bertos NR, Gilquin B, Chan GKT, Yen TJ, Khochbin S, Yang XJ. Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention. J Biol Chem. 2004;279(46):48246-54.
Kerr E, Holohan C, McLaughlin KM, Majkut J, Dolan S, Redmond K, et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ. 2012;19(8):1317-27.
Zhang X, Yuan Z, Zhang Y, Yong S, Salas-Burgos A, Koomen J, et al. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell. 2007;27(2):197-213.
Lienlaf M, Perez-Villarroel P, Knox T, Pabon M, Sahakian E, Powers J, et al. Essential role of HDAC6 in the regulation of PD-L1 in melanoma. Mol Oncol. 2016;10(5):735-50.
Ding G, Liu HD, Huang Q, Liang HX, Ding ZH, Liao ZJ, et al. HDAC6 promotes hepatocellular carcinoma progression by inhibiting P53 transcriptional activity. FEBS Lett. 2013;587(7):880-6.
Hsieh YL, Tu HJ, Pan SL, Liou JP, Yang CR. Anti-metastatic activity of MPT0G211, a novel HDAC6 inhibitor, in human breast cancer cells in vitro and in vivo. Biochim Biophys Acta Mol Cell Res. 2019;1866(6):992-1003.
Simões-Pires C, Zwick V, Nurisso A, Schenker E, Carrupt PA, Cuendet M. HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs? Mol Neurodegener. 2013;8(1):1-16.
Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 2007;447(7146):859-63.
d'Ydewalle C, Krishnan J, Chiheb DM, van Damme P, Irobi J, Kozikowski AP, et al. HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-tooth disease. Nat Med. 2011;17(8):968-74.
Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, et al. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007;178(6):1025-38.
Du Y, Seibenhener ML, Yan J, Jiang J, Wooten MC. aPKC phosphorylation of HDAC6 results in increased deacetylation activity. PLoS One. 2015;10(4):e0123191.
Williams KA, Zhang M, Xiang S, Hu C, Wu JY, Zhang S, et al. Extracellular signal-regulated kinase (ERK) phosphorylates histone deacetylase 6 (HDAC6) at serine 1035 to stimulate cell migration. J Biol Chem. 2013;288(46):33156-70.
Chen S, Owens GC, Makarenkova H, Edelman DB. HDAC6 regulates mitochondrial transport in hippocampal neurons. PLoS One. 2010;5(5):e10848.
Ustinova K, Novakova Z, Saito M, Meleshin M, Mikesova J, Kutil Z, et al. The disordered N-terminus of HDAC6 is a microtubule-binding domain critical for efficient tubulin deacetylation. J Biol Chem. 2020;295(9):2614-28.
Meszaros B, Erdos G, Dosztanyi Z. IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding. Nucleic Acids Res. 2018;46(W1):W329-37.
Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN. PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta. 2010;1804(4):996-1010.
Ouyang H, Ali YO, Ravichandran M, Dong A, Qiu W, MacKenzie F, et al. Protein aggregates are recruited to aggresome by histone deacetylase 6 via unanchored ubiquitin C termini. J Biol Chem. 2012;287(4):2317-27.
Hook SS, Orian A, Cowley SM, Eisenman RN. Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Proc Natl Acad Sci USA. 2002;99(21):13425-30.
Tria G, Mertens HDT, Kachala M, Svergun DI. Advanced ensemble modelling of flexible macromolecules using X-ray solution scattering. IUCrJ. 2015;2(Pt 2):207-17.
Ortega A, Amoros D, Garcia de la Torre J. Prediction of hydrodynamic and other solution properties of rigid proteins from atomic- and residue-level models. Biophys J. 2011;101(4):892-8.
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596(7873):583-9.
Weiss MA, Ellenberger T, Wobbe CR, Lee JP, Harrison SC, Struhl K. Folding transition in the DMA-binding domain of GCN4 on specific binding to DNA. Nature. 1990;347(6293):575-8.
Borcherds W, Theillet FX, Katzer A, Finzel A, Mishall KM, Powell AT, et al. Disorder and residual helicity alter p53-Mdm2 binding affinity and signaling in cells. Nat Chem Biol. 2014;10(12):1000-2.
Matthews JM, Sunde M. Dimers, oligomers, everywhere. In: Matthews JM, editor. Protein dimerization and oligomerization in biology. New York, NY: Springer; 2012. p. 1-18.
Banks CAS, Zhang Y, Miah S, Hao Y, Adams MK, Wen Z, et al. Integrative modeling of a Sin3/HDAC complex sub-structure. Cell Rep. 2020;31(2):107516.
Guenther MG, Lane WS, Fischle W, Verdin E, Lazar MA, Shiekhattar R. A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev. 2000;14(9):1048-57.
Kelly RD, Cowley SM. The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochem Soc Trans. 2013;41(3):741-9.
Watson PJ, Fairall L, Santos GM, Schwabe JWR. Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature. 2012;481(7381):335-40.
Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 1999;13(15):1924-35.
Lee MG, Wynder C, Cooch N, Shiekhattar R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature. 2005;437(7057):432-5.
Luo Y, Jian W, Stavreva D, Fu X, Hager G, Bungert J, et al. Trans-regulation of histone deacetylase activities through acetylation. J Biol Chem. 2009;284(50):34901-10.
Kwon S, Zhang Y, Matthias P. The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes Dev. 2007;21(24):3381-94.
Matthias P, Yoshida M, Khochbin S. HDAC6 a new cellular stress surveillance factor. Cell Cycle. 2008;7(1):7-10.
Kuechler ER, Budzyńska PM, Bernardini JP, Gsponer J, Mayor T. Distinct features of stress granule proteins predict localization in membraneless organelles. J Mol Biol. 2020;432(7):2349-68.
Hofmann S, Kedersha N, Anderson P, Ivanov P. Molecular mechanisms of stress granule assembly and disassembly. Biochim Biophys Acta Mol Cell Res. 2021;1868(1):118876.
Zhang M, Xiang S, Joo HY, Wang L, Williams KA, Liu W, et al. HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Mol Cell. 2014;55(1):30-46.
Siahaan V, Krattenmacher J, Hyman AA, Diez S, Hernández-Vega A, Lansky Z, et al. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes. Nat Cell Biol. 2019;21(9):1086-92.
Henrichs V, Grycova L, Barinka C, Nahacka Z, Neuzil J, Diez S, et al. Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments. Nat Commun. 2020;11(1):3123.
Liu Y, Peng L, Seto E, Huang S, Qiu Y. Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity through acetylation. J Biol Chem. 2012;287(34):29168-74.
Kutay U, Guttinger S. Leucine-rich nuclear-export signals: born to be weak. Trends Cell Biol. 2005;15(3):121-4.
Stommel JM, Marchenko ND, Jimenez GS, Moll UM, Hope TJ, Wahl GM. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J. 1999;18(6):1660-72.
Kutil Z, Skultetyova L, Rauh D, Meleshin M, Snajdr I, Novakova Z, et al. The unraveling of substrate specificity of histone deacetylase 6 domains using acetylome peptide microarrays and peptide libraries. FASEB J. 2019;33(3):4035-45.
Plechanovova A, Jaffray EG, Tatham MH, Naismith JH, Hay RT. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature. 2012;489(7414):115-20.
Yang M, Hoeppner M, Rey M, Kadek A, Man P, Schriemer DC. Recombinant nepenthesin II for hydrogen/deuterium exchange mass spectrometry. Anal Chem. 2015;87(13):6681-7.
Trcka F, Durech M, Man P, Hernychova L, Muller P, Vojtesek B. The assembly and intermolecular properties of the Hsp70-Tomm34-Hsp90 molecular chaperone complex. J Biol Chem. 2014;289(14):9887-901.
Zhang Z, Smith DL. Determination of amide hydrogen exchange by mass spectrometry: a new tool for protein structure elucidation. Protein Sci. 1993;2(4):522-31.
Brautigam CA. Calculations and publication-quality illustrations for analytical ultracentrifugation data. Methods Enzymol. 2015;562:109-33.
Schuck P. Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and Lamm equation modeling. Biophys J. 2000;78(3):1606-19.
Schuck P. On the analysis of protein self-association by sedimentation velocity analytical ultracentrifugation. Anal Biochem. 2003;320(1):104-24.
Konermann L. Addressing a common misconception: ammonium acetate as neutral pH “buffer” for native electrospray mass spectrometry. J Am Soc Mass Spectrom. 2017;28(9):1827-35.
Hedges JB, Vahidi S, Yue X, Konermann L. Effects of ammonium bicarbonate on the electrospray mass spectra of proteins: evidence for bubble-induced unfolding. Anal Chem. 2013;85(13):6469-76.
van den Heuvel RH, van Duijn E, Mazon H, Synowsky SA, Lorenzen K, Versluis C, et al. Improving the performance of a quadrupole time-of-flight instrument for macromolecular mass spectrometry. Anal Chem. 2006;78(21):7473-83.
Hernandez H, Robinson CV. Determining the stoichiometry and interactions of macromolecular assemblies from mass spectrometry. Nat Protoc. 2007;2(3):715-26.
Krichel B, Bylapudi G, Schmidt C, Blanchet C, Schubert R, Brings L, et al. Hallmarks of alpha-and betacoronavirus non-structural protein 7+ 8 complexes. Sci Adv. 2021;7(10):eabf1004.
Marty MT, Baldwin AJ, Marklund EG, Hochberg GKA, Benesch JLP, Robinson CV. Bayesian deconvolution of mass and ion mobility spectra: from binary interactions to polydisperse ensembles. Anal Chem. 2015;87(8):4370-6.
Gotze M, Pettelkau J, Schaks S, Bosse K, Ihling CH, Krauth F, et al. StavroX - a software for analyzing crosslinked products in protein interaction studies. J Am Soc Mass Spectrom. 2012;23(1):76-87.
Blanchet CE, Spilotros A, Schwemmer F, Graewert MA, Kikhney A, Jeffries CM, et al. Versatile sample environments and automation for biological solution X-ray scattering experiments at the P12 beamline (PETRA III, DESY). J Appl Cryst. 2015;48(Pt 2):431-43.
Franke D, Kikhney AG, Svergun DI. Automated acquisition and analysis of small angle X-ray scattering data. Nucl Instrum Methods Phys Res Sect A. 2012;689:52-9.
Svergun DI. Determination of the regularization parameter in indirect-transform methods using perceptual criteria. J Appl Cryst. 1992;25(4):495-503.
Konarev PV, Volkov VV, Sokolova AV, Koch MH, Svergun DI. PRIMUS: a Windows PC-based system for small-angle scattering data analysis. J Appl Cryst. 2003;36(5):1277-82.
Hajizadeh NR, Franke D, Jeffries CM, Svergun DI. Consensus Bayesian assessment of protein molecular mass from solution X-ray scattering data. Sci Rep. 2018;8(1):7204.
Panjkovich A, Svergun DI. CHROMIXS: automatic and interactive analysis of chromatography-coupled small-angle X-ray scattering data. Bioinformatics. 2018;34(11):1944-6.
Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10(6):845-58.
Kavan D, Man P. MSTools-web based application for visualization and presentation of HXMS data. Int J Mass Spectrom. 2011;302(1-3):53-8.
RefSeq
NP_006035.2
