Key result
The A114N mutant of MyoD exhibits an altered conformation in the basic region that leads to a global change affecting the activation domain, suggesting defective conformation abolishes activation.
The study demonstrates that the activation domain of MyoD is unmasked only upon DNA binding by the correct basic region, suggesting a coupled conformational relationship.
Hypothesis-generating for MyoD allostery; leaves open relevance to human myogenesis or cardiac repair.
The MyoD family of basic helix-loop-helix (bHLH) proteins is required for myogenic determination and differentiation. The basic region carries the myogenic code and DNA binding specificity, while the N terminus contains a potent transcriptional activation domain. Myogenic activation is abolished when the basic region, bound to a myogenic E box, carries a mutation of Ala-114. It has been proposed that DNA binding of the MyoD basic region leads to recruitment of a recognition factor that unmasks the activation domain. Here we demonstrate that an A114N mutant exhibits an altered conformation in the basic region and that this local conformational difference can lead to a more global change affecting the conformation of the activation domain. This suggests that the deleterious effects of this class of mutations may result directly from defective conformation. Thus, the activation domain is unmasked only upon DNA binding by the correct basic region. Such a coupled conformational relationship may have evolved to restrict myogenic specificity to a small number of bHLH proteins among many with diverse functions yet with DNA binding specificities known to be similar.
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Huang et al. (1998) studied this question. A114N mutant of MyoD was evaluated on Conformational change in the basic region and activation domain. The A114N mutant of MyoD exhibits an altered conformation in the basic region that leads to a global change affecting the activation domain, suggesting defective conformation abolishes activation.
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