Molecular mechanism of specificity in promoter DNA recognition

May 2021: Published in Nuclear Acids Research, Neel Sarovar Bhavesh and collaborators in New Delhi elucidate the molecular basis of the RBMS1-promoter DNA interaction to understand the mechanism for specificity.

Understanding the specificity and affinity of protein-DNA interactions is a long-standing question, involving thermodynamics and kinetics. Evidence, however, remains scarce when answering crucial biological questions.

DNA binding proteins recognize DNA specifically or non-specifically using direct and indirect readout mechanisms like sliding, hopping, and diffusion. However, a common difficulty in explicitly elucidating any particular mechanism of site-specific DNA-protein recognition is the lack of knowledge regarding target sequences and inadequate account of non-specific interactions, in general. In this paper, Aggarwal and Bhavesh have deciphered the structural basis of target search performed by the key regulator of expression of c-myc proto-oncogene, the human RBMS1 protein and have shown the structural reorganization of this multi-domain protein required for recognizing the specific c-myc promoter sequence.

The work provides the first structural and dynamics characterization of human RBMS1 protein that controls the expression of c-myc proto-oncogene inside the human cell by its interaction with 7 base pair consensus sequence within the 21 bp promoter/ autonomous origin of replication region 2 kb upstream of c-myc proto-oncogene.

The results suggest that a synergy between structural re-organization and thermodynamics is necessary for the recognition of target sequences. The study thereby presents another perspective of looking at the DNA-protein interactions.

Further reading

Aggarwal, P. and Bhavesh, NS. Hingle like domain motion facilitates human RBMS1 protein binding to proto-oncogene c-myc promoter. Nucleic Acids Res (2021). Molecular mechanisms of specificity in promoter DNA recognition (English and Hindi)

From Figure 3. (A) X-ray structure of the c-myc promoter bound to RBMS1 protein (58–224) and its symmetry related molecules. (B) The electron density omit map of DNA at 1σ in the bound form with the stacking distance of 3.7 Å between A1 and T2 nucleotides is shown. (C) Zoomed in view of DNA binding between protein and one symmetry related molecule. (D) The interactions between the amino acid residues of the linker and the DNA nucleotides of promoter DNA sequence are shown. (E) Superimposition of the solution-state NMR structure of apo RBMS1 with the crystal structure of RBMS1 bound with DNA showing the opening of the 310-helix in the linker region and movement of the RRM2 domain to bind DNA.