Tetrapeptide KEDW Interacts with DNA and Regulates Gene Expression

V.V. Ashapkin,^e P.P. Yakutseni,^h B.F. Vanyushin^e

^bKarolinska University Hospital, Solna, Stockholm, Sweden.

^c Pavlov Institute of Physiology, the Russian Academy of Sciences, St-Petersburg, Russian Federation.

^dSaint-Petersburg Institute of Bioregulation and Gerontology, St-Petersburg, Russia.

^eBelozersky Institute of Physical and Chemical Biology, M.V. Lomonosov Moscow State University, Moscow, Russian Federation.

^f Saint-Petersburg State University, Department of Physics, St-Petersburg, Russian Federation.

^gSaint-Petersburg State Polytechnic University, Department of Medical Physics, St.-Petersburg, Russian Federation.

^hSaint-Petersburg Polytechnic University, Center for Advanced Studies, St-Petersburg, Russian Federation.

^*Corresponding Author

Prof. V.Kh. Khavinson

Pavlov Institute of Physiology

the Russian Academy of Sciences

St-Petersburg, 199034

Russian Federation.

E-mail: khavinson@gerontology.ru

Abstract

Peptide KEDW (Lys-Glu-Asp-Trp-NH2) is known to reduce the blood glucose level in rats with streptozotocin- and alloxan-induced diabetes mellitus. Here, we examine the influence of KEDW peptide on cell differentiation and DNA structure. KEDW peptide increased the expression of PDX1, NGN3, PAX6, FOXA2, NKX2-2, NKX6.1, and PAX4 genes but decreased MNX1 and HOXA3 gene expression when added to pancreatic cell culture. Moreover, KEDW peptide caused an increase in expression of PDX1, NGN3, PAX6, FOXA2, NKX2-2, NKX6.1, and PAX4 proteins without affecting synthesis of MNX1 and HOXA3 when added to pancreatic cell culture. Results obtained through physical methods (UV–visible absorption, circular dichroism) and molecular modelling methods suggest that the peptide binds to DNA along the major groove. Experimental and theoretical data provided a 3D model of the stable DNA-peptide complex. We propose that regulation of differentiation factor expression in pancreatic (endocrine) cells by KEDW peptide occurs through specific binding of the peptide to regulatory elements of corresponding genes.

Keywords: KEDW peptide, diabetes mellitus, gene expression, protein synthesis, molecular modelling, DNA binding.

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