Analysis of the Protein-Protein Interaction of CREBBP, HTT, and KMT2D by Principal Components Method

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Abstract

The transcriptional coactivator CREBBP (cyclic AMP response element binding protein-binding protein), neuron-specific transcriptional regulator HTT (huntingtin) and histone-lysine methyltransferase KMT2D (lysine methyltransferase 2D) cooperatively participate in post-translational modification of histones and regulation of differential gene expression. The mechanism of protein-protein interactions has been poorly studied. Computer analysis of the primary structure of proteins using the principal components method revealed the presence of the highest possible correlation between the main components of amino acid sequences in the CREBBP–HTT and CREBBP–KMT2D pairs with glutamine. The trajectory of the first principal component of CREBBP practically coincides with the graph of the positional frequency of glutamine along the protein molecule. It is shown that in the secondary structure of CREBBP a significant share is occupied by E-strand (extended strand) elements with an open conformation of the peptide chain. Polyglutamine tracts localized at the C-terminus of CREBBP, N′-terminus of HTT, N-, C-termini and in the center of KMT2D also have an open conformation facilitating the formation of intermolecular hydrogen bonds. It is assumed that the polyglutamine tracts of the C-terminus of CREBBP and the N-terminus of HTT are directly involved in the protein-protein contact of CREBBP–HTT. A similar connection between the polyglutamine tracts of the C-terminus of CREBBP and the central region of KMT2D fixes the physical interaction in this pair of proteins. The identified features of the studied proteins can be used to design new pharmacological drugs using physicochemical methods.

About the authors

I. I. Khegai

Institute of Cytology and Genetics Federal Research Center, Siberian Branch, Russian Academy of Sciences

Email: khegay@bionet.nsc.ru
Novosibirsk, Russia

R. Gong

Institute of Cytology and Genetics Federal Research Center, Siberian Branch, Russian Academy of Sciences

Novosibirsk, Russia

V. M. Efimov

Institute of Cytology and Genetics Federal Research Center, Siberian Branch, Russian Academy of Sciences

Novosibirsk, Russia

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