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bioRxiv · 10.1101/057489

Phylogenetic and structural analyses reveal the determinants of DNA binding specificities of nucleoid-associated proteins HU and IHF

Debayan Dey·Valakunja Nagaraja·Suryanarayanarao Ramakumar
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Abstract

Nucleoid-associated proteins (NAPs) are chromosome-organizing factors, which affect the transcriptional landscape of a bacterial cell. HU is an NAP, which binds to DNA with a broad specificity while homologous IHF (Integration Host Factor), binds DNA with moderately higher specificity. Specificity and differential binding affinity of HU/IHF proteins towards their target binding sites play a crucial role in their regulatory dynamics. Decades of biochemical and genomic studies have been carried out for HU and IHF like proteins. Yet, questions related to their DNA binding specificity, and differential ability to bend DNA thus affecting the binding site length remained unanswered. In addition, the problem has not been investigated from an evolutionary perspective. Our phylogenetic analysis revealed three major clades belonging to HU, IHF and IHF{beta} like proteins with reference to E. coli. We carried out a comparative analysis of three-dimensional structures of HU/IHF proteins to gain insight into the structural basis of clade division. The present study revealed three major features which contribute to differential DNA binding specificity of HU/IHF proteins, I) conformational restriction of DNA binding residues due to salt-bridge formation II) the enrichment of alanine in the DNA binding site increasing conformational space of flexible side chains in its vicinity and III) nature of DNA binding residue (Arg to Lys bias in different clades) which interacts differentially to DNA bases. Differences in the dimer stabilization strategies between HU and IHF were also observed. Our analysis reveals a comprehensive evolutionary picture, which rationalizes the origin of multi-specificity of HU/IHF proteins using sequence and structure-based determinants, which could also be applied to understand differences in binding specificities of other nucleic acid binding proteins.

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Debayan Dey, Valakunja Nagaraja, Suryanarayanarao Ramakumar. 2016-06-07. Phylogenetic and structural analyses reveal the determinants of DNA binding specificities of nucleoid-associated proteins HU and IHF. https://doi.org/10.1101/057489

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