Abstract
Surprisingly few transcription factors drive animal development relative to the number and diversity of final tissues and body structures. Therefore, most transcription factors must function in more than one tissue. In a famous example, members of the Hox transcription factor family are expressed in contiguous stripes along the anterior/posterior axis during animal development. Individual Hox transcription factors specify all tissues within their expression domain and thus must respond to cellular cues to instigate the correct tissue-specific gene regulatory cascade. We describe how, in the Drosophila Hox protein Ultrabithorax, intrinsically disordered regions implement, regulate and co-ordinate multiple functions, potentially enabling context-specific gene regulation. The large N-terminal disordered domain encodes most of the transcription activation domain and directly impacts DNA binding affinity by the Ubx homeodomain. Similarly, the C-terminal disordered domain alters DNA binding affinity and specificity, interaction with a Hox binding protein and strongly influences both transcription activation and repression. Phosphorylation of the N-terminal disordered domain and alternative splicing of the C-terminal disordered domain could allow the cell to both regulate and co-ordinate DNA binding, protein interactions and transcription regulation. For regulatory mechanisms relying on disorder to continue to be available when Ubx is bound to other proteins or DNA, fuzziness would need to be preserved in these macromolecular complexes. The intrinsically disordered domains in Hox proteins are predicted to be on the very dynamic end of the disorder spectrum, potentially allowing disorder to persist when Ubx is bound to proteins or DNA to regulate the function of these “fuzzy” complexes. Because both intrinsically disordered regions within Ubx have multiple roles, each region may implement several different regulatory mechanisms identified in fuzzy complexes. These intrinsic disorder-based regulatory mechanisms are likely to be critical for allowing Ubx to sense tissue identity and respond by implementing a context-specific gene regulatory cascade.
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References
Kriwacki RW, Hengst L, Tennant L et al. Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. Proc Natl Acad Sci USA 1996; 93:11504–11509.
Tompa P, Szász C, Buday L. Structural disorder throws new light on moonlighting. Trends Biochem Sci 2005; 30:484–489.
Romero PR, Zaidi S, Fang YY et al. Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci USA 2006; 103:8390–8395.
Vilasi S, Ragone R. Abundance of intrinsic disorder in SV-IV, a multifunctional androgen-dependent protein secreted from rat seminar vesicle. FEBS J 2008; 275:763–774.
Iakoucheva LM, Radivojac P, Brown CJ et al. The importance of intrinsic disorder for protein phosphorylation. Nucl Acids Res 2004; 32:1037–1049.
Lu X, Hamkalo B, Parseghian MH et al. Chromatin condensing functions of the linker histone C-terminal domain are mediated by specific amino acid composition and intrinsic protein disorder. Biochemistry 2009; 48:164–172.
Sandhu KS. Intrinsic disorder explains diverse nuclear roles of chromatin remodeling proteins. J Mol Recognit 2009; 22:1–8.
Galea CA, Wang Y, Sivakolundu SG et al. Regulation of cell division by intrinsically unstructured proteins: intrinsic flexibility, modularity and signaling conduits. Biochemistry 2008; 47:7598–7609.
Liu Y, Matthews KS, Bondos SE. Multiple intrinsically disordered sequences alter DNA binding by the homeodomain of the Drosophila Hox protein Ultrabithorax. J Biol Chem 2008; 283:20874–20887.
Liu Y, Matthews KS, Bondos SE. Internal regulatory interactions determine DNA binding specificity by a Hox transcription factor. J Mol Biol 2009; 390:760–774.
Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by Notch. Dev Cell 2009; 16:196–208.
Liu J, Perumal NB, Oldfield CJ et al. Intrinsic disorder in transcription factors. Biochemistry 2006; 45:6873–6888.
Ward JJ, Sodhi JS, McGuffin LJ et al. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 2004; 337:635–645.
Tompa P, Fuxreiter M. Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 2008; 33:2–8.
Halder G, Callaerts P, Gehring WJ. Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 1995; 267:1788–1792.
Lo PCH, Frasch M. Establishing A-P polarity in the embryonic heart tube: a conserved function of Hox genes in Drosophila and vertebrates. Trends Cardiovasc Med 2003; 13:182–187.
Hughes CL, Kaufman TC. Hox genes and the evolution of the arthropod body plan. Evol Dev 2002; 4:459–499.
Lewis EB. A gene complex controlling segmentation in Drosophila. Nature 1978; 276:565–570.
Gellon G, McGinnis W. Shaping animal body plans in development and evolution by modulation of Hox expression patterns. Bio Essays 1998; 20:116–125.
Pearson JC, Lemons D, McGinnis W. Modulating Hox gene functions during animal body patterning. Nature Rev Genet 2005; 6:893–904.
Bondos SE, Tan XX. Combinatorial transcription regulation: the interaction of transcription factors and cell signaling molecules with homeodomain proteins in Drosophila development. Crit Rev Euk Gene Express 2001; 11:145–171.
Mann RS, Lelli KM, Joshi R. Hox specificity: unique roles for cofactors and collaborators. Curr Topics Dev Biol 2009; 88:63–101.
Bienz M. Homeotic genes and positional signaling in the Drosophila viscera. Trends Genet 1994; 10:22–26.
Rivilin PK, Gong A, Schneiderman AM et al. The role of Ultrabithorax in the patterning of adult thoracic muscles in Drosophila melanogaster. Dev Genes Evol 2001; 211:55–66.
Rogulja-Ortmann A, Renner S, Technau GM. Antagonistic roles for Ultrabithorax and Antennapedia in regulating segment-specific apoptosis of differentiated motoneurons in the Drosophila embryonic central nervous system. Development 2008; 135:3435–3445.
Graba Y, Aragnol D, Pradel J. Drosophila Hox complex downstream targets and the function of homeotic genes. BioEssays 1997; 19:379–388.
Capovilla M, Brandt M, Botas J. Direct regulation of decapentaplegic by Ultrabithorax and its role in Drosophila midgut morphogenesis. Cell 1994; 76:461–475.
de Navas LF, Garulet DL, Sánchez-Herrero E. The Ultrabithorax Hox gene of Drosophila controls haltere size by regulating the Dpp pathway. Development 2006; 133:4495–4506.
Weatherbee SD, Halder G, Kim J et al. Ultrabithorax regulates genes at several levels of the wing-patterning hierarchy to shape the development of the Drosophila haltere. Genes Dev 1998; 12:1474–1482.
Bondos SE, Catanese DJ Jr, Tan XX et al. Hox transcription factor Ultrabithorax Ib physically and genetically interacts with Disconnected Interacting Protein 1, a double-stranded RNA-binding protein. J Biol Chem 2004; 279:26433–26444.
Bondos SE, Tan XX, Matthews KS. Physical and genetic interactions link Hox function with diverse transcription factors and cell signaling proteins. Mol Cell Proteomics 2006; 5:824–834.
Chan SK, Jaffe L, Capovilla M et al. The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with Extradenticle, another homeoprotein. Cell 1994; 78:603–615.
Tan XX, Bondos S, Li L et al. Transcription activation by Ultrabithorax Ib requires a predicted a-helical region. Biochemistry 2002; 41:2774–2785.
López AJ, Artero RD, Perez-Alonso M. Stage, tissue and cell specific distribution of alternative Ultrabithorax mRNAs and protein isoforms in the Drosophila embryo. Roux’s Arch Dev Biol 1996; 205:450–459.
Mann RS, Hogness DS. Functional dissection of Ultrabithorax proteins in D. melanogaster. Cell 1990; 60:597–610.
Subramaniam V, Bomze HM, López AJ. Functional differences between Ultrabithorax protein isoforms in Drosophila melanogaster: evidence from elimination, substitution and ectopic expression of specific isoforms. Genetics 1994; 136:979–991.
Reed HC, Hoare T, Thomsen S. Alternative splicing modulates Ubx protein function in Drosophila melanogaster. Genetics 2010; 184:745–758.
Bomze HM, López AJ. Evolutionary conservation of the structure and expression of alternatively spliced Ultrabithorax isoforms from Drosophila. Genetics 1994; 136:965–977.
Merabet S, Hudry B, Saadaoui M et al. Classification of sequence signatures: a guide to Hox protein function. BioEssays 2009; 31:500–511.
Jones DT, Taylor WR, Thornton JM. The rapid generation of mutation data matrices from protein sequences. Compt Appl Biosci 1992; 8:275–282.
White SH. Global statistics of protein sequences: implications for the origin, evolution and prediction of protein structure. Annu Rev Biophys Biomol Struct 1994; 23:407–439.
Tourasse NJ, Li WH. Selective constraints, amino acid composition and the rate of protein evolution. Mol Biol Evol 2000; 17:656–664.
Brooks DJ, Fresco JR. Increased frequency of cysteine, tyrosine and phenylalanine since the last universal ancestor. Mol Cell Proteomics 2002; 1:125–131.
Hubbard S, Benyon RJ. Proteolysis of native proteins as a structural probe. In: Benyon R, Bonds JS, eds. Proteolytic Enzymes, 2nd edition. Oxford: Oxford University Press, 2001:248–249.
López AJ, Hogness DS. Immunochemical dissection of the Ultrabithorax homeoprotein family in Drosophila melanogaster. Proc Natl Acad Sci USA 1991; 88:9924–9928.
White RAH, Wilcox M. Protein products of the bithorax complex in Drosophila. Cell 1984; 39:163–171.
Hegedus T, Serohijos AWR, Dokholyan NV et al. Computational studies reveal phosphorylation-dependent changes in the unstructured R domain of CFTR. J Mol Biol 2008; 378:1052–1063.
Bondos SE, Bicknell A. Detection and prevention of protein aggregation before, during and after purification. Anal Bioch 2003; 316:223–231.
Passner JM, Ryoo HD, Shen L et al. Structure of a DNA-bound Ultrabithorax-Extradenticle homeodomain complex. Nature 1999; 397:714–719.
Bridges CB, Morgan TH. The third-chromosome group of mutant characters of Drosophila melanogaster. Publs Carnegie Instn 1923; 327:1–251.
Garber RL, Kuroiwa A, Gehring WJ. Genomic and cDNA clones of the homeotic locus Antennapedia in Drosophila. EMBO J 1983; 2:2027–2036.
Scott MP, Weiner AJ, Polisky BA et al. The molecular organization of the Antennapedia complex of Drosophila. Cell 1983; 35:763–776.
McGinnis W, Levine MS, Hafen E et al. A conserved DNA sequence in homeotic genes of the Drosophila antennapedia and bithorax complexes. Nature 1984; 308:428–433.
McGinnis W, Garber RL, Wirz J et al. A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans. Cell 1984; 37:403–408.
Hersh BM, Nelson CE, Stoll SJ et al. The UBX-regulated network in the haltere imaginal disc of D. melanogaster. Dev Biol 2007; 302:717–727.
Carr A, Biggin MD. A comparison of in vivo and in vitro DNA-binding specificities suggests a new model for homeoprotein DNA binding in Drosophila embryos. EMBO J 1999; 18:1598–1608.
Mastick GS, McKay R, Oligino T et al. Identification of target genes regulated by homeotics proteins in Drosophila melanogaster through genetic selection of Ultrabithorax protein-binding sites in yeast. Genetics 1995; 139:349–363.
Zhai Z, Stein MAS, Lohmann I. Expression of the apoptosis gene reaper in homeotic, segmentation and other mutants in Drosophila. Gene Expr Patterns 2009; 9:357–363.
Damante G, Pelizzari L, Esposito G et al. A molecular code dictates sequence-specific DNA recognition by homeodomains. EMBO J 1996; 15:4992–5000.
Berger MF, Badis G, Gehrke AR. Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 2008; 133:1266–1276.
Noyes MB, Christensen RG, Wakabayashi A et al. Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell 2008; 133:1277–1289.
Ekker SC, Young E, von Kessler DP et al. Optimal DNA sequence recognition by the Ultrabithorax homeodomain of Drosophila. EMBO J 1991; 10:1179–1186.
Ekker SC, Jackson DG, von Kessler DP et al. The degree of variation in DNA sequence recognition among four Drosophila homeotic proteins. EMBO J 1994; 13:3551–3560.
Frazee RW, Taylor JA, Tulius TD. Interchange of DNA-binding modes in the deformed and Ultrabithorax homeodomain of Drosophila. EMBO J 2002; 10:1179–1186.
Gutmanas A, Billeter M. Specific DNA recognition by the Antp homeodomain: MD simulations of specific and nonspecific complexes. Proteins 2004; 57:772–782.
Hoey T, Levine M. Divergent homeo box proteins recognize similar DNA seuqneces in Drosophila. Nature 1988; 332:858–861.
Kalionis B, O’Farrell PH. A universal target sequence is bound in vitro by diverse homeodomains. Mech Dev 1993; 43:57–70.
Gehring WJ, Qian YQ, Billeter M et al. Homeodomain-DNA recognition. Cell 1994; 78:211–223.
Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Ann Rev Biochem 2009; 78:273–304.
Gavis ER, Hogness DS. Phosphorylation, expression and function of the Ultrabithorax protein family in Drosophila melanogaster. Development 1991; 112:1077–1093.
Li L, von Kessler D, Beachy PA et al. pH-dependent enhancement of DNA binding by the Ultrabithorax homeodomain. Biochemistry 1996; 35:9832–9839.
Tour E, Hittinger CT, McGinnis W. Evolutionarily conserved domains required for activation and repression functions of the Drosophila Hox protein Ultrabithorax. Development 2005; 132:5271–5281.
Chan SK, Pöpperl H, Krumlauf R et al. An Extradenticle-induced conformational change in a Hox protein overcomes an inhibitory function of the conserved hexapeptide motif. EMBO J 1996; 15:2476–2487.
Li X, Murre C, McGinnis W. Activity regulation of a Hox protein and a role for the homeodomain in inhibiting transcriptional activation. EMBO J 1999; 18:198–211.
Garza AS, Ahmad N, Kumar R. Role of intrinsically disordered protein regions/domains in transcriptional regulation. Life Sci 2009; 84:189–193.
Krasnow MA, Saffman EE, Kornfeld K et al. Transcriptional activation and repression by Ultrabithorax proteins in cultured Drosophila cells. Cell 1989; 57:1031–1043.
Galant R, Carroll SB. Evolution of a transcriptional repression domain in an insect Hox protein. Nature 2002; 415:910–913.
Ronshaugen M, McGinnis N, McGinnis W. Hox protein mutation and the macroevolution of the insect body plan. Nature 2002; 415:914–917.
Pinsonneault J, Florence B, Vaessin H et al. A model for Extradenticle-induced function as a switch that changes Hox proteins from repressors to activators. EMBO J 1997; 16:2032–2042.
Saleh M, Rammbaldi I, Yang XJ et al. Cell signaling switches Hox-Pbx complexes from repressors to activators of transcription. Mol Cell Biol 2000; 20:8623–8633.
Merabet S, Kambris Z, Capovilla M et al. The hexapeptide and linker regions of the AbdA Hox protein regulate its activating and repressive functions. Dev Cell 2003; 4:761–768.
Merabet S, Saadaoui M, Sambrani N et al. A unique Extradenticle recruitment mode in the Drosophila Hox protein Ultrabithorax. Proc Natl Acad Sci USA 2007; 104:16946–16951.
Mann RS, Chan SK. Extra specificity from Extradenticle: the partnership between HOX and PBX/EXD homeodomain proteins. Trends Genet 1996; 12:258–262.
Mann RS, Affolter M. Hox proteins meet more partners. Curr Opin Genet Dev 1998; 8:423–429.
van Dijk MA, Murre C. Extradenticle raises the DNA binding specificity of homeotic selector gene products. Cell 1994; 78:617–624.
Heuber SD, Lohmann I. Shaping segments: Hox gene function in the genomic age. BioEssays 2008; 30:965–979.
Merabet S, Pradel J, Graba Y. Getting a molecular grasp on Hox contextual activity. Trends Genet 2005; 21:477–480.
Xu L. Regulation of Smad activities. Biochem Biophys Acta 2006; 1759:503–513.22.
Walsh CM, Carroll SB. Collaboration between Smads and a Hox protein in target gene repression. Development 2007; 134:3585–3592.
Verheyen EM, Gottardi CJ. Regulation of Wnt/betal-Catenin signaling by protein kinases. Dev Dyn 2010; 239:34–44.
Johnson FB, Parker E, Krasnow MA. Extradenticle protein is a selective cofactor for the Drosophila homeotics: role of the homeodomain and YPWM amino acid motif in the interaction. Proc Natl Acad Sci USA 1995; 92:739–743.
Shanmugan K, Featherstone MS, Saragovi HU. Residues flanking the HOX YPWM motif contribute to cooperative interactions with PBX. J Biol Chem 1997; 272:19081–19087.
Asahara H, Dutta S, Kao HY et al. Pbx-Hox heterodimers recruit coactivator-corepressor complexes in an isoform-specific manner. Mol Cell Biol 1999; 19:8219–8225.
Haynes C, Oldfield CJ, Ji F et al. Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comp Biol 2006; 8:890–901.
Hilser VJ, Thompson EB. Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins. Proc Natl Acad Sci USA 2007; 104:8311–8315.
Dunker AK, Cortese MS, Romero P. Flexible nets: the roles of intrinsic disorder in protein interaction networks. FEBS J 2005; 272:5129–5148.
Hall J, Karplus PA, Barbar E. Multivalency in the assembly of intrinsically disordered dynein intermediate chain. J Biol Chem 2009; 48:33115–33121.
Beachy PA, Varkey J, Young KE et al. Cooperative binding of an Ultrabithorax homeodomain protein to nearby and distant DNA sites. Mol Cell Biol 1993; 13:6941–6956.
Gebelein B, Culi J, Ryoo HD et al. Specificity of Distalless repression and limb primordia development by Abdominal Hox proteins. Dev Cell 2002; 3:487–498.
Gebelein B, McKay DJ, Mann RS. Direct integration of Hox and segmentation gene inputs during Drosophila development. Nature 2004; 431:653–659.
Sun B, Hursh DA, Jackson D et al. Ultrabithorax protein is necessary but not sufficient for full activation of decapentaplegic expression in the visceral mesoderm. EMBO J 1995; 14:520–535.
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Bondos, S.E., Hsiao, HC. (2012). Roles for Intrinsic Disorder and Fuzziness in Generating Context-specific Function in Ultrabithorax, a Hox Transcription Factor. In: Fuxreiter, M., Tompa, P. (eds) Fuzziness. Advances in Experimental Medicine and Biology, vol 725. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0659-4_6
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