3AY5

Crystal structure of HHM (human homologue of murine maternal Id-like molecule)

Summary for 3AY5

• Entry DOI: 10.2210/pdb3ay5/pdb
• Descriptor: Cyclin-D1-binding protein 1 (2 entities in total)
• Functional Keywords: dominant-negative helix-loop-helix transcriptional regulator, cell cycle
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O95273
• Total number of polymer chains: 1
• Total formula weight: 40269.70

Authors

Seto, A.,Ishitani, R.,Nureki, O. (deposition date: 2011-04-28, release date: 2012-03-14, Last modification date: 2024-03-13)

Primary citation

Ishii, R.,Isogaya, K.,Seto, A.,Koinuma, D.,Watanabe, Y.,Arisaka, F.,Yaguchi, S.,Ikushima, H.,Dohmae, N.,Miyazono, K.,Miyazawa, K.,Ishitani, R.,Nureki, O.
Structure of a dominant-negative helix-loop-helix transcriptional regulator suggests mechanisms of autoinhibition.
Embo J., 31:2541-2552, 2012

PubMed Abstract: 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.

PubMed: 22453338
DOI: 10.1038/emboj.2012.77

Experimental method

X-RAY DIFFRACTION (2.5 Å)