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43  structures 1653  species 1  interaction 13830  sequences 125  architectures

Family: HLH (PF00010)

Summary: Helix-loop-helix DNA-binding domain

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This is the Wikipedia entry entitled "Basic helix-loop-helix". More...

Basic helix-loop-helix Edit Wikipedia article

basic helix-loop-helix DNA-binding domain
Basic helix loop helix.png
Basic helix-loop-helix structural motif of ARNT. Two α-helices (blue) are connected by a short loop (red).[1]
Identifiers
Symbol bHLH
Pfam PF00010
InterPro IPR001092
SMART SM00353
PROSITE PDOC00038
SCOP 1mdy
SUPERFAMILY 1mdy

A basic helix-loop-helix (bHLH) is a protein structural motif that characterizes a family of transcription factors.[2][3][4] It should not be confused with the helix-turn-helix domain.

Structure

The motif is characterized by two α-helices connected by a loop. In general, transcription factors including this domain are dimeric, each with one helix containing basic amino acid residues that facilitate DNA binding.[5] In general, one helix is smaller, and, due to the flexibility of the loop, allows dimerization by folding and packing against another helix. The larger helix typically contains the DNA-binding regions. bHLH proteins typically bind to a consensus sequence called an E-box, CANNTG.[6] The canonical E-box is CACGTG (palindromic), however some bHLH transcription factors, notably those of the bHLH-PAS family, bind to related non-palindromic sequences, which are similar to the E-box.

Examples

Examples of transcription factors containing a bHLH include:

bHLH transcription factors are often important in development or cell activity. BMAL1-Clock is a core transcription complex in the molecular circadian clock. Other genes, like c-Myc and HIF-1, have been linked to cancer due to their effects on cell growth and metabolism.

Regulation

Since many bHLH transcription factors are heterodimeric, their activity is often highly regulated by the dimerization of the subunits. One subunit's expression or availability is often controlled, whereas the other subunit is constitutively expressed. Many of the known regulatory proteins, such as the Drosophila extramacrochaetae protein, have the helix-loop-helix structure but lack the basic region, making them unable to bind to DNA on their own. They are, however, able to form heterodimers with proteins that have the bHLH structure, and inactivate their abilities as transcription factors.[7]

History

  • 1989: Murre et al. showed that dimers of various bHLH proteins bind to a short DNA motif (later called E-Box).[8] This E-box consists of the DNA sequence CANNTG, where N can be any nucleotide.[6]
  • 1994: Harrison's[9] and Pabo's[10] groups crystallize bHLH proteins bound to E-boxes, demonstrating that the parallel 4-helix bundle motif loop orients the basic sequences to interact with specific nucleotides in the major groove of the E-box.
  • 1994: Wharton et al. identified asymmetric E-boxes bound by a subset of bHLH proteins with PAS domains (bHLH-PAS proteins), including Single-minded (Sim) and the aromatic hydrocarbon receptor.[11]
  • 1995: Semenza's group identifies hypoxia-inducible factor (HIF) as a bHLH-PAS heterodimer that binds a related asymmetric E-box.[12]
  • 2009: Grove, De Masi et al., identified novel short DNA motifs, bound by a subset of bHLH proteins, which they defined as "E-box-like sequences". These are in the form of CAYRMK, where Y stands for C or T, R is A or G, M is A or C and K is G or T.[13]

Human proteins with helix-loop-helix DNA-binding domain

AHR; AHRR; ARNT; ARNT2; ARNTL; ARNTL2; ASCL1; ASCL2; ASCL3; ASCL4; ATOH1; ATOH7; ATOH8; BHLHB2; BHLHB3; BHLHB4; BHLHB5; BHLHB8; CLOCK; EPAS1; FERD3L; FIGLA; HAND1; HAND2; HES1; HES2; HES3; HES4; HES5; HES6; HES7; HEY1; HEY2; HIF1A; ID1; ID2; ID3; ID4; KIAA2018; LYL1; MASH1; MATH2; MAX; MESP1; MESP2; MIST1; MITF; MLX; MLXIP; MLXIPL; MNT; MSC; MSGN1; MXD1; MXD3; MXD4; MXI1; MYC; MYCL1; MYCL2; MYCN; MYF5; MYF6; MYOD1; MYOG; NCOA1; NCOA3; NEUROD1; NEUROD2; NEUROD4; NEUROD6; NEUROG1; NEUROG2; NEUROG3; NHLH1; NHLH2; NPAS1; NPAS2; NPAS3; OAF1; OLIG1; OLIG2; OLIG3; PTF1A; SCL; SCXB; SIM1; SIM2; SOHLH1; SOHLH2; SREBF1; SREBF2; TAL1; TAL2; TCF12; TCF15; TCF21; TCF3; TCF4; TCFL5; TFAP4; TFE3; TFEB; TFEC; TWIST1; TWIST2; USF1; USF2;

References

  1. ^ PDB 1x0o; Card PB, Erbel PJ, Gardner KH (October 2005). "Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization". J. Mol. Biol. 353 (3): 664–77. doi:10.1016/j.jmb.2005.08.043. PMID 16181639. 
  2. ^ Murre C, Bain G, van Dijk MA, Engel I, Furnari BA, Massari ME, Matthews JR, Quong MW, Rivera RR, Stuiver MH (June 1994). "Structure and function of helix-loop-helix proteins". Biochim. Biophys. Acta 1218 (2): 129–35. doi:10.1016/0167-4781(94)90001-9. PMID 8018712. 
  3. ^ Littlewood TD, Evan GI (1995). "Transcription factors 2: helix-loop-helix". Protein Profile 2 (6): 621–702. PMID 7553065. 
  4. ^ Massari ME, Murre C (January 2000). "Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms". Mol. Cell. Biol. 20 (2): 429–40. doi:10.1128/MCB.20.2.429-440.2000. PMC 85097. PMID 10611221. 
  5. ^ Lawrence Zipursky; Arnold Berk; Monty Krieger; Darnell, James E.; Lodish, Harvey F.; Kaiser, Chris; Matthew P Scott; Matsudaira, Paul T. McGill Lodish 5E Package - Molecular Cell Biology & McGill Activation Code. San Francisco: W. H. Freeman. ISBN 0-7167-8635-4. 
  6. ^ a b Chaudhary J, Skinner MK (1999). "Basic helix-loop-helix proteins can act at the E-box within the serum response element of the c-fos promoter to influence hormone-induced promoter activation in Sertoli cells". Mol. Endocrinol. 13 (5): 774–86. doi:10.1210/me.13.5.774. PMID 10319327. 
  7. ^ Cabrera CV, Alonso MC, Huikeshoven H (1994). "Regulation of scute function by extramacrochaete in vitro and in vivo". Development 120 (12): 3595–603. PMID 7821225. 
  8. ^ Murre C, McCaw PS, Vaessin H et al. (1989). "Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence". Cell 58 (3): 537–44. doi:10.1016/0092-8674(89)90434-0. PMID 2503252. 
  9. ^ Ellenberger T, Fass D, Arnaud M, Harrison SC (April 1994). "Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer". Genes Dev. 8 (8): 970–80. doi:10.1101/gad.8.8.970. PMID 7926781. 
  10. ^ Ma PC, Rould MA, Weintraub H, Pabo CO (May 1994). "Crystal structure of MyoD bHLH domain-DNA complex: perspectives on DNA recognition and implications for transcriptional activation". Cell 77 (3): 451–9. doi:10.1016/0092-8674(94)90159-7. PMID 8181063. 
  11. ^ Wharton KA, Franks RG, Kasai Y, Crews ST (December 1994). "Control of CNS midline transcription by asymmetric E-box-like elements: similarity to xenobiotic responsive regulation". Development 120 (12): 3563–9. PMID 7821222. 
  12. ^ Wang GL, Jiang BH, Rue EA, Semenza GL (June 1995). "Hypoxia-inducible factor 1 is a basic helix-loop-helix-PAS heterodimer regulated by cellular O2 tension". Proc. Natl. Acad. Sci. U.S.A. 92 (12): 5510–4. doi:10.1073/pnas.92.12.5510. PMC 41725. PMID 7539918. 
  13. ^ Grove C, De Masi F et al. (2009). "A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors". Cell 138 (2): 314–27. doi:10.1016/j.cell.2009.04.058. PMC 2774807. PMID 19632181. 

External links

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Helix-loop-helix DNA-binding domain Provide feedback

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Literature references

  1. Littlewood TD, Evan GI; , Protein Profile 1995;2:621-702.: Transcription factors 2: helix-loop-helix. PUBMED:7553065 EPMC:7553065


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR011598

The helix-loop-helix (HLH) DNA-binding domain consists of a closed bundle of four helices in a left-handed twist with two crossover connections. The HLH domain directs dimerisation, and is juxtaposed to basic regions to create a DNA interaction interface surface that recognises specific DNA sequences. Basic region/HLH (bHLH) proteins regulate diverse biological pathways [PUBMED:10710415]. bHLH proteins include MyoD [PUBMED:12783965], SREBPs (sterol regulatory element binding proteins) [PUBMED:9634703], and yeast Pho4 (phosphatase system) [PUBMED:9303313].

In certain proteins the bHLH domain contains a leucine-zipper motif. The bHLH/leucine zipper (bHLHZip) domain specifies dimerisation within a network of proteins and determines sequence-specific DNA binding [PUBMED:10378692]. bHLHZip domains occur in the transcription factors Myc, Mad, Max and Usf [PUBMED:12553908, PUBMED:8306960].

This entry is bHLHZip, which covers the bHLH domain and the leucine zipper motif, when present.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

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  Seed
(164)
Full
(13830)
Representative proteomes NCBI
(12625)
Meta
(9)
RP15
(1550)
RP35
(2941)
RP55
(4943)
RP75
(7025)
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  Seed
(164)
Full
(13830)
Representative proteomes NCBI
(12625)
Meta
(9)
RP15
(1550)
RP35
(2941)
RP55
(4943)
RP75
(7025)
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Curation and family details

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Curation View help on the curation process

Seed source: Unknown
Previous IDs: none
Type: Domain
Author: Eddy SR
Number in seed: 164
Number in full: 13830
Average length of the domain: 53.50 aa
Average identity of full alignment: 29 %
Average coverage of the sequence by the domain: 14.63 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.7 20.7
Trusted cut-off 20.7 20.7
Noise cut-off 20.6 20.6
Model length: 55
Family (HMM) version: 21
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Species distribution

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Interactions

There is 1 interaction for this family. More...

HLH

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HLH domain has been found. There are 43 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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