| First Author | Ishii R | Year | 2012 |
| Journal | EMBO J | Volume | 31 |
| Issue | 11 | Pages | 2541-52 |
| PubMed ID | 22453338 | Mgi Jnum | J:184710 |
| Mgi Id | MGI:5426104 | Doi | 10.1038/emboj.2012.77 |
| Citation | Ishii R, et al. (2012) Structure of a dominant-negative helix-loop-helix transcriptional regulator suggests mechanisms of autoinhibition. EMBO J 31(11):2541-52 |
| abstractText | Helix-loop-helix (HLH) family transcription factors regulate numerous developmental and homeostatic processes. Dominant-negative HLH (dnHLH) proteins lack DNA-binding ability and capture basic HLH (bHLH) transcription factors to inhibit cellular differentiation and enhance cell proliferation and motility, thus participating in patho-physiological processes. We report the first structure of a free-standing human dnHLH protein, HHM (Human homologue of murine maternal Id-like molecule). HHM adopts a V-shaped conformation, with N-terminal and C-terminal five-helix bundles connected by the HLH region. In striking contrast to the common HLH, the HLH region in HHM is extended, with its hydrophobic dimerization interfaces embedded in the N- and C-terminal helix bundles. Biochemical and physicochemical analyses revealed that HHM exists in slow equilibrium between this V-shaped form and the partially unfolded, relaxed form. The latter form is readily available for interactions with its target bHLH transcription factors. Mutations disrupting the interactions in the V-shaped form compromised the target transcription factor specificity and accelerated myogenic cell differentiation. Therefore, the V-shaped form of HHM may represent an autoinhibited state, and the dynamic conformational equilibrium may control the target specificity. |
