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Figure 4 | Molecular Cancer

Figure 4

From: miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias

Figure 4

Molecular Modeling and docking studies of wild-type and mutant KLF4 . (A) Representative sequence alignment of wild-type KLF4 (derived from control T-cells) with mutant KLF4 (derived from pediatric T-ALL samples). The zinc finger motifs Zf1, Zf2 and Zf3 are highlighted and (*) indicates conserved residues. The grey region indicates third zinc finger motif (Zf3) with mutated amino acids. (B-C) The structure of zinc finger motifs for wild type (B) and mutant KLF4 (C) were built using MODELLER Program under Accelrys Discovery Studio version 2.5. Zf1; blue, Zf2; green and Zf3; red. Comparison of structural models of the third zinc-finger motif between wild-type and mutant KLF4 revealed the amino acid replacements C462V, C465M, and H482F, which were involved in coordination with zinc (D) Superimposition of Zf3 motif of wild-type (pink) and mutant KLF4 ( blue). (E) Molecular interaction of modeled wild-type and mutant KLF4 with its target DNA binding sequence with inserted table depicting the binding energies of the interacting complexes. (F-G) Docking analysis of wild-type KLF4 revealed that residues R458, K453, R471and R467 displayed cation-π interactions with guanine (at positions 11, 6, 7) and cytidine 10. In contrast, docking of mutant KLF4 with its target DNA sequence exhibited cation-π interactions only between R443 and cytidine 14. (H) Docking analysis of wild-type KLF4 revealed that residues H424 and S470 formed hydrogen bonds with guanine (at positions 20 and 11), respectively. Such interactions were missing in mutant KLF4 as a consequence of altered sequence of KLF4 third zinc finger motif; R458 only formed a hydrogen bond with guanine 3. See Additional file 3: Figure S3 (I) β-galactosidase reporter activity in control and T-ALL lymphoblasts transfected with β-gal construct. The experiments were repeated thrice and results were reported as relative β-gal activity. *P < 0.05 relative to control.

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