An overview of the basic helix-loop-helix proteins

Table 1 Classification of bHLH proteins by sequence

Phylogenetic group	Description	Classification according to Murre et al. [12]	Examples of classified proteins (family names)
A	Bind to CAGCTG or CACCTG	I, II	MyoD, Twist, Net
B	Bind to CACGTG or CATGTTG	III, IV	Mad, Max, Myc
C	Bind to ACGTG or GCGTG. Contain a PAS domain		Single-minded, aryl hydrocarbon receptor nuclear translocator (Arnt), hypoxia-inducible factor (HIF), Clock
D	Lack a basic domain and hence do not bind DNA but form protein-protein dimers that function as antagonists of group A proteins	V	ID
E	Bind preferentially to N-box sequences CACGCG or CACGAG. Contain an orange domain and a WRPW peptide	VI	Hairy
F	Contain an additional COE domain, involved in dimerization and DNA binding		Coe (Col/Olf-1/EBF)

This classification of bHLH proteins is based on sequence comparisons, E-box binding, conservation of residues in parts of the protein other than the bHLH region and the presence or absence of additional domains. It was first adopted by Atchley and Fitch [13] and extended by Ledent and coworkers [6]. The older classification based on tissue distributions, DNA-binding specificities and dimerization, proposed by Murre and coworkers for a much smaller set of sequences [12], is shown for comparison.