Structural effect of the L16Q, K50E, and R53P mutations on homeodomain of pituitary homeobox protein 2

International Journal of Biological Macromolecules
M Rajasekaran, Chinpan Chen

Abstract

The transcription factor pituitary homeobox protein 2 (PITX2) is involved in genetic control of development. Mutations in PITX2, most in the homeodomain, cause the autosomal-dominant disorder Rieger syndrome. The mutants L16Q, K50E and R53P destabilize the structure and disrupt DNA-binding activity. The biological functions of these mutants have been characterized but not the structural basis behind the loss of DNA-binding activity. We performed multiple molecular dynamics simulations at 37°C to investigate the structural and dynamic effects of the 3 PITX2 homeodomain mutants. Compared with the wild type (WT), the L16Q mutant induces a kink in the α3 helix, which is stabilized by the hydrogen bond of Q21-R59. The disruption in backbone hydrogen bonds of V47-N51 and W48-R52 leads to a kink formation in the α3 helix of K50E. The R53P mutant alters the relative orientation of helices, which is apparently stabilized by the formation of new hydrogen bonds of T38-Q11, T38-Q12, T38-R2, N39-R2, L40-Q1, L40-R2, and T41-Q4. The hydrophobic core residues F8, L13, L40 and V45 change their positions in all mutants to break the hydrophobic core. Thus, changes in helical orientations and hydrophobic core cause rearrangement of the DNA-binding...Continue Reading

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Citations

Sep 1, 2015·Biologicals : Journal of the International Association of Biological Standardization·Saeme AsgariAzadeh Ebrahim-Habibi
Dec 13, 2017·Journal of Cellular Biochemistry·Senthilkumar Balaraman, Rajasekaran Ramalingam
Sep 7, 2016·Bioinformatics and Biology Insights·Subhomoi BorkotokyAyaluru Murali

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