helix loop helix motifs


Summary: Recurring supersecondary structures characterized by 20 amino acids folding into two alpha helices connected by a non-helical "loop" segment. They are found in many sequence-specific DNA-BINDING PROTEINS and in CALCIUM-BINDING PROTEINS.

Top Publications

  1. Sugimori M, Nagao M, Bertrand N, Parras C, Guillemot F, Nakafuku M. Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development. 2007;134:1617-29 pubmed
    ..We propose a molecular code model whereby the combinatorial actions of two classes of transcription factors coordinately regulate the domain-specific temporal sequence of neurogenesis and gliogenesis in the developing spinal cord. ..
  2. Firulli B, Howard M, McDaid J, McIlreavey L, Dionne K, Centonze V, et al. PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation. Mol Cell. 2003;12:1225-37 pubmed
    ..Mutations in phosphorylated residues result in altered HAND1 dimerization and biological function. Taken together, these results suggest that site-specific phosphorylation regulates HAND factor functional specificity. ..
  3. Kewley R, Whitelaw M, Chapman Smith A. The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol. 2004;36:189-204 pubmed
    ..Similarly, it is anticipated that developing a detailed mechanistic and structural understanding of bHLH/PAS proteins will ultimately facilitate drug design. ..
  4. Lee S, Sekimoto T, Yamashita E, Nagoshi E, Nakagawa A, Imamoto N, et al. The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor. Science. 2003;302:1571-5 pubmed
    ..Importin-beta changes its conformation to reveal a pseudo-twofold symmetry on its surface structure so that it can accommodate a symmetric dimer molecule. Importin-beta may use a similar strategy to recognize other dimeric cargoes. ..
  5. Amoutzias G, Robertson D, Oliver S, Bornberg Bauer E. Convergent evolution of gene networks by single-gene duplications in higher eukaryotes. EMBO Rep. 2004;5:274-9 pubmed
  6. Coppe J, Itahana Y, Moore D, Bennington J, Desprez P. Id-1 and Id-2 proteins as molecular markers for human prostate cancer progression. Clin Cancer Res. 2004;10:2044-51 pubmed
    ..We propose that both Id-1 and Id-2 proteins control prostate cancer cell phenotypes and could serve as molecular markers of aggressive human prostate cancer. ..
  7. Firulli A. A HANDful of questions: the molecular biology of the heart and neural crest derivatives (HAND)-subclass of basic helix-loop-helix transcription factors. Gene. 2003;312:27-40 pubmed
  8. Ruzinova M, Benezra R. Id proteins in development, cell cycle and cancer. Trends Cell Biol. 2003;13:410-8 pubmed
    ..Thus, the Id proteins have become important molecules for understanding basic biological processes as well as targets for potential therapeutic intervention in human disease. ..
  9. Fong S, Debs R, Desprez P. Id genes and proteins as promising targets in cancer therapy. Trends Mol Med. 2004;10:387-92 pubmed

More Information


  1. Vervoort M, Ledent V. The evolution of the neural basic Helix-Loop-Helix proteins. ScientificWorldJournal. 2001;1:396-426 pubmed
    ..e., the partitioning of ancestral expression patterns among the duplicates and, by extension, we propose that subfunctionalization is a key process to understand the evolution of neural bHLH genes. ..
  2. Hill A, Riley P. Differential regulation of Hand1 homodimer and Hand1-E12 heterodimer activity by the cofactor FHL2. Mol Cell Biol. 2004;24:9835-47 pubmed
  3. Firulli B, Krawchuk D, Centonze V, Vargesson N, Virshup D, Conway S, et al. Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities. Nat Genet. 2005;37:373-81 pubmed publisher
  4. Quan X, Hassan B. From skin to nerve: flies, vertebrates and the first helix. Cell Mol Life Sci. 2005;62:2036-49 pubmed
    ..This review will focus on current studies of neural development in vertebrate and invertebrate PNS and on understanding how the bHLH domain structure encodes multiple functions required for neural specification. ..
  5. Perk J, Iavarone A, Benezra R. Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer. 2005;5:603-14 pubmed publisher
  6. Lasorella A, Iavarone A. The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system. Proc Natl Acad Sci U S A. 2006;103:4976-81 pubmed
    ..These data indicate that ENH contributes to differentiation of the nervous system through cytoplasmic sequestration of Id2. They also suggest that ENH is a restraining factor of the oncogenic activity of Id proteins in neural tumors. ..
  7. Simionato E, Ledent V, Richards G, Thomas Chollier M, Kerner P, Coornaert D, et al. Origin and diversification of the basic helix-loop-helix gene family in metazoans: insights from comparative genomics. BMC Evol Biol. 2007;7:33 pubmed
    ..We suggest that these features may be extended to other developmental gene families and reflect a general trend in the evolution of the developmental gene repertoires of metazoans. ..
  8. Toledo Ortiz G, Huq E, Quail P. The Arabidopsis basic/helix-loop-helix transcription factor family. Plant Cell. 2003;15:1749-70 pubmed
    ..These data are consistent, in principle, with the operation of this combinatorial mechanism in Arabidopsis. ..
  9. Buck M, Atchley W. Phylogenetic analysis of plant basic helix-loop-helix proteins. J Mol Evol. 2003;56:742-50 pubmed
    ..We suggest that plant bHLH proteins are under weaker selective constraints than their animal counterparts and that lineage specific expansions and subfunctionalization have fashioned regulatory proteins for plant specific functions. ..
  10. Jones S. An overview of the basic helix-loop-helix proteins. Genome Biol. 2004;5:226 pubmed
    ..In animals, they are important regulators of embryonic development, particularly in neurogenesis, myogenesis, heart development and hematopoiesis. ..
  11. Desprez P, Sumida T, Coppe J. Helix-loop-helix proteins in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2003;8:225-39 pubmed
    ..The purpose of this review is to summarize the evidence implicating HLH proteins in the regulation of normal and transformed mammary epithelial cell phenotypes. ..
  12. Sigvardsson M, Clark D, Fitzsimmons D, Doyle M, Akerblad P, Breslin T, et al. Early B-cell factor, E2A, and Pax-5 cooperate to activate the early B cell-specific mb-1 promoter. Mol Cell Biol. 2002;22:8539-51 pubmed
    ..Together, our studies demonstrate the complexity of factors regulating tissue-specific transcription and support the concept that EBF, E2A, and Pax-5 cooperate to activate target genes in early B-cell development. ..
  13. Crozatier M, Glise B, Vincent A. Connecting Hh, Dpp and EGF signalling in patterning of the Drosophila wing; the pivotal role of collier/knot in the AP organiser. Development. 2002;129:4261-9 pubmed
    ..A model recapitulating the molecular interplay between the Hh, Dpp and EGF signalling pathways in the wing AP organiser is presented...
  14. Fukuma M, Okita H, Hata J, Umezawa A. Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma. Oncogene. 2003;22:1-9 pubmed
    ..In the present study, we suggest that Id2 is a target of the chimeric proteins and that the c-myc/Id2 pathway plays a pivotal role in the tumorigenic processes provoked by EWS/ets proteins. ..
  15. Schindl M, Schoppmann S, Strobel T, Heinzl H, Leisser C, Horvat R, et al. Level of Id-1 protein expression correlates with poor differentiation, enhanced malignant potential, and more aggressive clinical behavior of epithelial ovarian tumors. Clin Cancer Res. 2003;9:779-85 pubmed
    ..Consequently, Id-1 inhibition in the future might be of benefit for patients with ovarian cancer. ..
  16. Jean François N, Frédéric G, Raymund W, Benoit C, Lavigne P. Improving the thermodynamic stability of the leucine zipper of max increases the stability of its b-HLH-LZ:E-box complex. J Mol Biol. 2003;326:1577-95 pubmed
    ..A formalism to characterize the temperature-dependence of the unfolding, including the effect of intermediates, is presented. ..
  17. Heim M, Jakoby M, Werber M, Martin C, Weisshaar B, Bailey P. The basic helix-loop-helix transcription factor family in plants: a genome-wide study of protein structure and functional diversity. Mol Biol Evol. 2003;20:735-47 pubmed
    ..Based on the current characterization of a limited number of plant bHLH proteins, we predict that this family of TFs has a range of different roles in plant cell and tissue development as well as plant metabolism. ..
  18. Satou Y, Imai K, Levine M, Kohara Y, Rokhsar D, Satoh N. A genomewide survey of developmentally relevant genes in Ciona intestinalis. I. Genes for bHLH transcription factors. Dev Genes Evol. 2003;213:213-21 pubmed
  19. Lignell M, Becker H. Recognition and binding of a helix-loop-helix peptide to carbonic anhydrase occurs via partly folded intermediate structures. Biophys J. 2010;98:425-33 pubmed publisher
    ..We conclude that binding of the peptide to carbonic anhydrase involves a transition from a disordered to an ordered structure of the helix-loop-helix scaffold. ..
  20. Noffz C, Liedschulte V, Lengeler K, Ernst J. Functional mapping of the Candida albicans Efg1 regulator. Eukaryot Cell. 2008;7:881-93 pubmed publisher
  21. Groszmann M, Paicu T, Smyth D. Functional domains of SPATULA, a bHLH transcription factor involved in carpel and fruit development in Arabidopsis. Plant J. 2008;55:40-52 pubmed publisher
    ..Because the VP16 activation domain can compensate to some extent for the loss of the amphipathic helix and acidic domain, these domains may normally interact with such co-activators. ..
  22. Reddy M, Gokulan K, Jacobs W, Ioerger T, Sacchettini J. Crystal structure of Mycobacterium tuberculosis LrpA, a leucine-responsive global regulator associated with starvation response. Protein Sci. 2008;17:159-70 pubmed
    ..This study provides insights into the potential role of LrpA as a global regulator in the transition of M. tuberculosis to a persistent state. ..
  23. Sciarra A. Neuroendocrine differentiation in prostate adenocarcinoma. Eur Urol. 2007;52:1373 pubmed
  24. Shamloo M, Soriano L, von Schack D, Rickhag M, Chin D, Gonzalez Zulueta M, et al. Npas4, a novel helix-loop-helix PAS domain protein, is regulated in response to cerebral ischemia. Eur J Neurosci. 2006;24:2705-20 pubmed
    ..This could indicate a novel regulatory mechanism for activation and/or deactivation of this protein in response to ischemic brain injury. ..
  25. Zang M, Li Y, Xue L, Jia H, Jing H. Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C. J Cell Biochem. 2004;93:1255-66 pubmed
  26. Ellermeier C, Slauch J. RtsA and RtsB coordinately regulate expression of the invasion and flagellar genes in Salmonella enterica serovar Typhimurium. J Bacteriol. 2003;185:5096-108 pubmed
    ..Repression of the positive activators flhDC decreases expression of the entire flagellar regulon. We propose that RtsA and RtsB coordinate induction of invasion and repression of motility in the small intestine. ..
  27. Lee Y, Lee H, Park J, Yoo E, Glackin C, Choi Y, et al. Twist2, a novel ADD1/SREBP1c interacting protein, represses the transcriptional activity of ADD1/SREBP1c. Nucleic Acids Res. 2003;31:7165-74 pubmed
  28. Tipney H, Hinsley T, Brass A, Metcalfe K, Donnai D, Tassabehji M. Isolation and characterisation of GTF2IRD2, a novel fusion gene and member of the TFII-I family of transcription factors, deleted in Williams-Beuren syndrome. Eur J Hum Genet. 2004;12:551-60 pubmed
    ..Deletion mapping studies using somatic cell hybrids show that some WBS patients are hemizygous for this gene, suggesting that it could play a role in the pathogenesis of the disorder. ..
  29. Privalsky M. Activation incarnate. Dev Cell. 2003;5:1-2 pubmed
    ..Three new publications reveal that the nuclear receptors LRH-1, DHR38, and Nurr1 can assume active conformations in the absence of a ligand agonist. These reports help elucidate how transcriptional regulators are themselves regulated. ..
  30. Lin J, Hu Y, Tian B, Hua Y. Evolution of double MutT/Nudix domain-containing proteins: similar domain architectures from independent gene duplication-fusion events. J Genet Genomics. 2009;36:603-10 pubmed publisher
    ..Independent gene duplication-fusion events resulted in similar domain architectures of different double MutT/Nudix domain proteins. ..
  31. Kienker P, Jakes K, Finkelstein A. Identification of channel-lining amino acid residues in the hydrophobic segment of colicin Ia. J Gen Physiol. 2008;132:693-707 pubmed publisher
  32. Powell L, Deaton A, Wear M, Jarman A. Specificity of Atonal and Scute bHLH factors: analysis of cognate E box binding sites and the influence of Senseless. Genes Cells. 2008;13:915-29 pubmed publisher
    ..Moreover, the proneural cofactor, Senseless, can augment the function of Sc and Ato on their cognate E boxes and therefore may contribute to proneural specificity. ..
  33. Fukuda S, Kondo T, Takebayashi H, Taga T. Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway. Cell Death Differ. 2004;11:196-202 pubmed
    ..Together, these results reveal a novel molecular function of OLIG2 on the astrocyte development. Cell Death and Differentiation (2004) 11, 196-202. doi:10.1038/sj.cdd.4401332 Published online 24 October 2003 ..
  34. Muir T, Wilson Rawls J, Stevens J, Rawls A, Schweitzer R, Kang C, et al. Integration of CREB and bHLH transcriptional signaling pathways through direct heterodimerization of the proteins: role in muscle and testis development. Mol Reprod Dev. 2008;75:1637-52 pubmed publisher
    ..The observations suggest a mechanism for direct cross-talk between cAMP induced and bHLH controlled cellular differentiation...
  35. Chan A, Tsui W, Chen X, Chu K, Chan T, Chan A, et al. Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma. Oncogene. 2003;22:6946-53 pubmed
    ..The significant association of ID4 and hMLH1 promoter hypermethylation suggested that ID4 may also be among the genes being targeted in the CpG island methylator phenotype tumorigenic pathway. ..
  36. Catala M. [Neurosurgical embryology. Part 1: Cell differentiation]. Neurochirurgie. 2003;49:421-30 pubmed
    ..The second event is due to cell interactions (namely inductions). These inductions may be explained either by cell-cell contact (favored by cell adhesion molecules) or by secreting factors that can be either hydrophilic or lipophilic. ..
  37. Ramsay R, Malaterre J. Insights into c-Myb functions through investigating colonic crypts. Blood Cells Mol Dis. 2007;39:287-91 pubmed
    ..These observations, when combined with the understanding of c-Myb action in blood cells, is providing a clearer view as to how c-Myb operates in normal cells and how this is subverted in diseases like cancer. ..
  38. Ciccarelli F, Izaurralde E, Bork P. The PAM domain, a multi-protein complex-associated module with an all-alpha-helix fold. BMC Bioinformatics. 2003;4:64 pubmed
  39. Bylund M, Andersson E, Novitch B, Muhr J. Vertebrate neurogenesis is counteracted by Sox1-3 activity. Nat Neurosci. 2003;6:1162-8 pubmed
    ..These data suggest that the generation of neurons from stem cells depends on the inhibition of Sox1-3 expression by proneural proteins. ..
  40. Cai J, Goodman B, Patel A, Mulliken J, Van Maldergem L, Hoganson G, et al. Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening. Hum Genet. 2003;114:68-76 pubmed
    ..The risk for developmental delay in patients with deletions involving the TWIST gene is approximately 90% or eight times more common than in patients with intragenic mutations. ..
  41. Qian W, Tan G, Liu H, He S, Gao Y, An C. Identification of a bHLH-type G-box binding factor and its regulation activity with G-box and Box I elements of the PsCHS1 promoter. Plant Cell Rep. 2007;26:85-93 pubmed
    ..The results indicated that PsGBF bound with the G-box, but not the Box I element. Moreover, this combination effect of G-box and Box I only associated with PsGBF but not with other bHLH-type proteins such as OsMYC. ..
  42. de Candia P, Akram M, Benezra R, Brogi E. Id4 messenger RNA and estrogen receptor expression: inverse correlation in human normal breast epithelium and carcinoma. Hum Pathol. 2006;37:1032-41 pubmed
    ..Further investigations are required to define the functions of Id4 in the human normal breast and in mammary neoplasia. ..
  43. Yano Y, Ogura M, Matsuzaki K. Measurement of thermodynamic parameters for hydrophobic mismatch 2: intermembrane transfer of a transmembrane helix. Biochemistry. 2006;45:3379-85 pubmed
  44. Unzai S, Park S, Tame J. [Crystal structure of heme binding protein, an autotransporter hemoglobin protease from pathogenic Escherichia coli]. Tanpakushitsu Kakusan Koso. 2005;50:1322-7 pubmed
  45. deGraffenried L, Hopp T, Valente A, Clark R, Fuqua S. Regulation of the estrogen receptor alpha minimal promoter by Sp1, USF-1 and ERalpha. Breast Cancer Res Treat. 2004;85:111-20 pubmed
    ..Based upon these findings, we propose a possible model for transcription from the ERalpha minimal promoter. ..
  46. Nakada Y, Parab P, Simmons A, Omer Abdalla A, Johnson J. Separable enhancer sequences regulate the expression of the neural bHLH transcription factor neurogenin 1. Dev Biol. 2004;271:479-87 pubmed
    ..Thus, sequences are identified that can be used to direct temporally and spatially restricted expression of heterologous genes to the developing neural tube. ..
  47. Shida T, Furuya M, Nikaido T, Kishimoto T, Koda K, Oda K, et al. Aberrant expression of human achaete-scute homologue gene 1 in the gastrointestinal neuroendocrine carcinomas. Clin Cancer Res. 2005;11:450-8 pubmed
    ..These findings revealed that hASH1 is distinctly up-regulated in gastrointestinal NECs. hASH1 may be used as a more sensitive and specific marker than conventional pan-endocrine markers for clinical diagnosis of gastrointestinal NECs. ..
  48. Ohara T, Tsuge T. FoSTUA, encoding a basic helix-loop-helix protein, differentially regulates development of three kinds of asexual spores, macroconidia, microconidia, and chlamydospores, in the fungal plant pathogen Fusarium oxysporum. Eukaryot Cell. 2004;3:1412-22 pubmed
    ..However, the mutants produced markedly fewer macroconidia and microconidia in infected plants than the wild type. These results suggest that FoSTUA also has an important role for microconidium formation specifically in infected plants. ..
  49. Pin R, Reinblatt M, Bowers W, Federoff H, Fong Y. Herpes simplex virus amplicon delivery of a hypoxia-inducible angiogenic inhibitor blocks capillary formation in hepatocellular carcinoma. J Gastrointest Surg. 2004;8:812-22; discussion 822-3 pubmed
    ..the control group (P < 0.000001). HSV amplicon-mediated delivery of a hypoxia-inducible soluble VEGF receptor substantially reduces new vessel formation and tumor growth in hepatoma. ..
  50. Bessho Y, Hirata H, Masamizu Y, Kageyama R. Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev. 2003;17:1451-6 pubmed
    ..Thus, periodic repression by Hes7 protein is critical for the cyclic transcription of Hes7 and Lfng, and this negative feedback represents a molecular basis for the segmentation clock. ..
  51. Hernandez J, Heine G, Irani N, Feller A, Kim M, Matulnik T, et al. Different mechanisms participate in the R-dependent activity of the R2R3 MYB transcription factor C1. J Biol Chem. 2004;279:48205-13 pubmed
    ..Together, these findings suggest a model in which combinatorial interactions with co-activators enable R2R3 MYB factors with very similar DNA binding preferences to discriminate between target genes in vivo. ..
  52. Neelapu S, Baskar S, Gause B, Kobrin C, Watson T, Frye A, et al. Human autologous tumor-specific T-cell responses induced by liposomal delivery of a lymphoma antigen. Clin Cancer Res. 2004;10:8309-17 pubmed
  53. Liu R, Cai J, Hu X, Tan M, Qi Y, German M, et al. Region-specific and stage-dependent regulation of Olig gene expression and oligodendrogenesis by Nkx6.1 homeodomain transcription factor. Development. 2003;130:6221-31 pubmed
    ..In the hindbrain, unlike in the spinal cord, Olig1 and Olig2 can be expressed both inside and outside the Nkx6.1-expressing domains and oligodendrogenesis in this region is not dependent on Nkx6.1 activity. ..