Identifying the Substrate Interactions of KDAC7

Abstract

Protein post‐translational modifications are chemical adaptations that take place in the human body to control behavior of proteins. The acetylation of lysine is one type of protein post‐translational modification. Lysine deacetylases (KDACs or HDACs), are enzymes that help regulate proteins by reversing this modification. It has been shown that KDAC7 is essential in many biological processes, but KDAC7 has no identified substrate proteins. Therefore, better understanding of KDAC7 substrate preferences could lead to the improved treatment of diseases. Using a gain‐of‐function variant of KDAC7 that significantly increases enzyme activity, we have identified several possible substrates using peptides derived from identified acetylated proteins. Molecular dynamics simulations suggest possible important interactions between these peptides and the enzyme. We are also examining the effect of the second, non‐catalytic domain of KDAC7 on substrate preferences and overall activity. Possible substrates identified by these experiments provide leads for cell‐based assays to determine in vivo substrates and/or binding partners. This work provides a greater understanding of how KDAC7 interacts with potential substrate proteins and the biological activity of the enzyme.Support or Funding InformationNIH TL4GM118968, UL1GM118967, 5G12MD007595, and R15GM129682; NSF CHE 1625993 and MCB 1817358; U. S. Army Research Laboratory and the U. S. Army Research Office W911NF1810450; and the Louisiana Cancer Research Consortium.