Structural insights into the mechanism of negative regulation of single HMG-box proteins by the acidic tail domain [Protein Structure and Folding]

September 4th, 2014 by Stott, K., Watson, M., Bostock, M. J., Mortensen, S. A., Travers, A., Grasser, K. D., Thomas, J. O.

The Drosophila and plant (maize) functional counterparts of the abundant vertebrate chromosomal protein HMGB1 (HMG-D and ZmHMGB1, respectively) differ from HMGB1 in having a single HMG box, and basic and acidic flanking regions that vary greatly in length and charge. We show that despite these variations, HMG-D and ZmHMGB1 exist in dynamic assemblies in which the basic HMG boxes and linkers associate with their intrinsically-disordered, predominantly acidic, tails in a manner analogous to that observed previously for HMGB1. The DNA-binding surfaces of the boxes and linkers are occluded in 'auto-inhibited' forms of the protein, which are in equilibrium with transient, more open structures that are 'binding-competent'. This strongly suggests that the mechanism of auto-inhibition may be a general one. HMG-D and ZmHMGB1 also differ from HMGB1 in having phosphorylation sites in their tail and linker regions. In both cases, in-vitro phosphorylation of serine residues within the acidic tail stabilises the assembled form, suggesting another level of regulation for interaction with DNA, chromatin and other proteins that is not possible for the uniformly acidic (hence unphosphorylatable) tail of HMGB1.
  • Posted in Journal of Biological Chemistry, Publications
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