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Biophysical changes of ATP binding pocket may explain loss of kinase activity in mutant DAPK3 in cancer: A molecular

Tarun Agarwal1, Nithyanan Annamalai2, Tapas Kumar Maiti1

  • 1Department of Biotechnology, Indian Institute of Technology, Kharagpur, West Bengal, Pin: 721302, India.

Gene
|January 10, 2016
PubMed

Insights

Mutations in death-associated protein kinase 3 (DAPK3) disrupt its ATP binding pocket, leading to reduced kinase activity and potentially promoting cancer progression. This study reveals structural changes underlying this loss of function.

Area of Science:

  • Molecular Biology
  • Biophysics
  • Cancer Biology

Background:

  • Death-associated protein kinase 3 (DAPK3) is a tumor suppressor involved in cell cycle regulation, proliferation, apoptosis, and autophagy.
  • Mutations in DAPK3, such as T112M, D161N, and P216S, are observed in cancer patients and linked to significantly reduced kinase activity.
  • The precise structural and biophysical mechanisms behind the decreased kinase activity of these DAPK3 mutants remain unclear.

Purpose of the Study:

  • To investigate the structural and biophysical variations in DAPK3 caused by T112M, D161N, and P216S mutations.
  • To elucidate the molecular mechanisms underlying the reduced kinase activity of these DAPK3 mutants.

Main Methods:

  • Molecular dynamic simulations were employed to analyze structural changes in DAPK3 mutants.
  • Analysis focused on variations within the ATP binding pocket and interactions of key kinase motifs.

Main Results:

  • Mutations induce significant structural alterations in DAPK3, primarily affecting flexible loops within the ATP binding pocket.
  • D161N and P216S mutations lead to the collapse of the ATP binding pocket via flexible loop invasion, impeding ATP binding.
  • T112M mutation causes outward distortion of flexible loops, reducing ATP binding potential.
  • Mutants exhibit loss of essential active kinase features, including proper HR/FD and DFG motif interactions, a structured hydrophobic spine, and Lys42-Glu64 salt bridge interaction.

Conclusions:

  • The observed structural changes in DAPK3 mutants provide a mechanistic explanation for their diminished kinase activity.
  • These findings highlight the role of structural integrity in DAPK3 function and its implications in cancer development.
Keywords:
ATP binding siteApoptosisAutophagyDeath associated protein kinase 3 (DAPK3)Molecular dynamic simulation

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