#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains


Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.


Vyšlo v časopise: Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains. PLoS Genet 7(10): e32767. doi:10.1371/journal.pgen.1002302
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002302

Souhrn

Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.


Zdroje

1. CarrollSB 2008 Evo-devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell 134 25 36

2. PearsonJCLemonsDMcGinnisW 2005 Modulating Hox gene functions during animal body patterning. Nat Rev Genet 6 893 904

3. Prud'hommeBGompelNCarrollSB 2007 Emerging principles of regulatory evolution. Proc Natl Acad Sci U S A 104 Suppl 1 8605 8612

4. RonshaugenMMcGinnisNMcGinnisW 2002 Hox protein mutation and macroevolution of the insect body plan. Nature 415 914 917

5. TourEHittingerCTMcGinnisW 2005 Evolutionarily conserved domains required for activation and repression functions of the Drosophila Hox protein Ultrabithorax. Development 132 5271 5281

6. GalantRCarrollSB 2002 Evolution of a transcriptional repression domain in an insect Hox protein. Nature 415 910 913

7. MerabetSHudryBSaadaouiMGrabaY 2009 Classification of sequence signatures: a guide to Hox protein function. Bioessays 31 500 511

8. MerabetSSaadaouiMSambraniNHudryBPradelJ 2007 A unique Extradenticle recruitment mode in the Drosophila Hox protein Ultrabithorax. Proc Natl Acad Sci U S A 104 16946 16951

9. ChanS-KMannRS 1993 The segment identity functions of Ultrabithorax are contained within its homeo domain and carboxy-terminal sequences. Genes Dev 7 796 811

10. MannRSLelliKMJoshiR 2009 Hox specificity unique roles for cofactors and collaborators. Curr Top Dev Biol 88 63 101

11. Merabet sSNPradelJGrabaY 2009 Regulation of Hox activity: insights from protein motifs. In Hox genes, studies form the 20th to 21st century Landes Bioscience

12. PeisajovichSGGarbarinoJEWeiPLimWA 2010 Rapid diversification of cell signaling phenotypes by modular domain recombination. Science 328 368 372

13. HueberSDLohmannI 2008 Shaping segments: Hox gene function in the genomic age. Bioessays 30 965 979

14. GehringWJKloterUSugaH 2009 Evolution of the Hox gene complex from an evolutionary ground state. Curr Top Dev Biol 88 35 61

15. WellikDM 2009 Hox genes and vertebrate axial pattern. Curr Top Dev Biol 88 257 278

16. TumpelSWiedemannLMKrumlaufR 2009 Hox genes and segmentation of the vertebrate hindbrain. Curr Top Dev Biol 88 103 137

17. KrumlaufR 2009 Hox Genes and Patterning in Mammals. Annu Rev Cell Dev Biol

18. GibsonGSchierALeMottePGehringWJ 1990 The specificities of Sex combs reduced and Antennapedia are defined by a distinct portion of each protein that includes the homeodomain. Cell 62 1087 1103

19. KuzioraMAMcGinnisW 1989 A homeodomain substitution changes the regulatory specificity of the Deformed protein in Drosophila embryo. Cell 59 563 571

20. ZengWAndrewDJMathiesLDHornerMAScottMP 1993 Ectopic expression and function of the Antp and Scr homeotic genes: The N terminus of the homeodomain is critical to functional specificity. Development 118 339 352

21. ChauvetSMerabetSBilderDScottMPPradelJ 2000 Distinct hox protein sequences determine specificity in different tissues. Proc Natl Acad Sci U S A 97 4064 4069

22. SaadaouiMMerabetSLitim-MecheriIArbeilleESambraniN 2011 Selection of distinct Hox-Extradenticle interaction modes fine-tunes Hox protein activity. Proc Natl Acad Sci U S A 108 2276 2281

23. BrandAPerrimonN 1993 Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118 401 415

24. GebeleinBCuliJRyooHDZhangWMannRS 2002 Specificity of distalless repression and limb primordia development by abdominal hox proteins. Dev Cell 3 487 498

25. GebeleinBMcKayDJMannRS 2004 Direct integration of Hox and segmentation gene inputs during Drosophila development. Nature 431 653 659

26. AppelBSakonjuS 1993 Cell-type-specific mechanisms of transcriptional repression by the homeotic gene products UBX and ABD-A in Drosophila embryos. EMBO J 12 1099 1109

27. GrienenbergerAMerabetSManakJIltisIFabreA 2003 Tgf{beta} signaling acts on a Hox response element to confer specificity and diversity to Hox protein function. Development 130 5445 5455

28. ManakJRMathiesLCScottMP 1994 Regulation of a decapentaplegic midgut enhancer by homeotic proteins. Development 120 3605 3619

29. CapovillaMBrandtMBotasJ 1994 Direct regulation of decapentaplegic by Ultrabithorax and its role in midugt morphogenesis. Cell 76 461 475

30. BroduVElstobPRGouldAP 2002 abdominal A specifies one cell type in Drosophila by regulating one principal target gene. Development 129 2957 2963

31. ChiangCYoungKEBeachyPA 1995 Control of Drosophila tracheal branching by the novel homeodomain gene unplugged, a regulatory target for genes of the bithorax complex. Development 121 3901 3912

32. MichelsonAM 1994 Muscle pattern diversification in Drosophila is determined by the autonomous function of homeotic genes in the embryonic mesoderm. Development 120 755 768

33. LewisEB 1978 A gene complex controlling segmentation in Drosophila. Nature 276 565 570

34. Sanchez-HerreroEVernosIMarcoRMorataG 1985 Genetic organization of Drosophila bithorax complex. Nature 313 108 113

35. BelloBCHirthFGouldAP 2003 A pulse of the Drosophila Hox protein Abdominal-A schedules the end of neural proliferation via neuroblast apoptosis. Neuron 37 209 219

36. BergerCPallaviSKPrasadMShashidharaLSTechnauGM 2005 Cyclin E acts under the control of Hox-genes as a cell fate determinant in the developing central nervous system. Cell Cycle 4 422 425

37. PerrinLMonierBPonzielliRAstierMSemerivaM 2004 Drosophila cardiac tube organogenesis requires multiple phases of Hox activity. Dev Biol 272 419 431

38. DixitRVijayraghavanKBateM 2008 Hox genes and the regulation of movement in Drosophila. Dev Neurobiol 68 309 316

39. KarlssonDBaumgardtMThorS 2010 Segment-specific neuronal subtype specification by the integration of anteroposterior and temporal cues. PLoS Biol 8 e1000368 doi:10.1371/journal.pbio.1000368

40. BilderDGrabaYScottMP 1998 Wnt and TGFbeta signals subdivide the AbdA Hox domain during Drosophila mesoderm patterning. Development 125 1781 1790

41. MerabetSKambrisZCapovillaMBerengerHPradelJ 2003 The Hexapeptide and Linker Regions of the AbdA Hox Protein Regulate Its Activating and Repressive Functions. Dev Cell 4 761 768

42. ChiangCYoungKEBeachyPA 1995 Control of Drosophila tracheal branching by the novel homeodomain gene unplugged, a regulatory target for genes of the bithorax complex. Development 121 3901 3912

43. VachonGCohenBPfeifleCMcGuffinMEBotasJ 1992 Homeotic genes of the bithorax complex repress limb development in the abdomen of the Drosophila embryo through the target gene Distal-less. Cell 71 437 450

44. GebeleinBCuliJRyooHDZhangWMannRS 2002 Specificity of Distalless repression and limb primordia development by abdominal Hox proteins. Dev Cell 3 487 498

45. RauskolbCWieschausE 1994 Coordinate regulation of downstream genes by extradenticle and the homeotic selector proteins. Embo J 13 3561 3569

46. PeiferMWieschausE 1990 Mutations in the Drosophila gene extradenticle affect the way specific homeo domain proteins regulate segmental identity. Genes Dev 4 1209 1223

47. CapovillaMBotasJ 1998 Functional dominance among Hox genes: repression dominates activation in the regulation of Dpp. Development 125 4949 4957

48. MerabetSEbnerAAffolterM 2005 The Drosophila Extradenticle and Homothorax selector proteins control branchless/FGF expression in mesodermal bridge-cells. EMBO Rep 6 762 768

49. RieckhofGECasaresFRyooHDAbu-ShaarMMannRS 1997 Nuclear translocation of extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein. Cell 91 171 183

50. StobePSteinMAHabring-MullerABezdanDFuchsAL 2009 Multifactorial regulation of a hox target gene. PLoS Genet 5 e1000412 doi:10.1371/journal.pgen.1000412

51. JoshiRPassnerJMRohsRJainRSosinskyA 2007 Functional specificity of a Hox protein mediated by the recognition of minor groove structure. Cell 131 530 543

52. MeijsingSHPufallMASoAYBatesDLChenL 2009 DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324 407 410

53. LohrUPickL 2005 Cofactor-interaction motifs and the cooption of a homeotic Hox protein into the segmentation pathway of Drosophila melanogaster. Curr Biol 15 643 649

54. BurkeACNelsonCEMorganBATabinC 1995 Hox genes and the evolution of vertebrate axial morphology. Development in press

55. Prud'hommeBGompelNRokasAKassnerVAWilliamsTM 2006 Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene. Nature 440 1050 1053

56. GompelNPrud'hommeBWittkoppPJKassnerVACarrollSB 2005 Chance caught on the wing: cis-regulatory evolution and the origin of pigment patterns in Drosophila. Nature 433 481 487

57. JeongSRebeizMAndolfattoPWernerTTrueJ 2008 The evolution of gene regulation underlies a morphological difference between two Drosophila sister species. Cell 132 783 793

58. JeongSRokasACarrollSB 2006 Regulation of body pigmentation by the Abdominal-B Hox protein and its gain and loss in Drosophila evolution. Cell 125 1387 1399

59. WilliamsTMSelegueJEWernerTGompelNKoppA 2008 The regulation and evolution of a genetic switch controlling sexually dimorphic traits in Drosophila. Cell 134 610 623

60. SivanantharajahLPercival-SmithA 2009 Analysis of the sequence and phenotype of Drosophila Sex combs reduced alleles reveals potential functions of conserved protein motifs of the Sex combs reduced protein. Genetics 182 191 203

61. HittingerCTSternDLCarrollSB 2005 Pleiotropic functions of a conserved insect-specific Hox peptide motif. Development 132 5261 5270

62. PrinceFKatsuyamaTOshimaYPlazaSResendez-PerezD 2008 The YPWM motif links Antennapedia to the basal transcriptional machinery. Development 135 1669 1679

63. SaeedAIBhagabatiNKBraistedJCLiangWSharovV 2006 TM4 microarray software suite. Methods Enzymol 411 134 193

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2011 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#