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The Signal Transducer and Activator of Transcription 3 (STAT3), the key protein in the JAK-STAT3 pathway, regulates the expression of several genes involved in cell proliferation, immune responses, and other essential cellular functions. Additionally, STAT3 impaired or constitutive activity has been associated with several diseases, including cancer. For its activation and dimerization, STAT3 undergoes to suffer several post-translational modifications, being the two most important, the acetylation of Lys685 and the phosphorylation of Tyr705. It has been shown that STAT3 has physical contact with the Histone Deacetylase 6 (HDAC6). The interaction between STAT3 and HDAC6 favors the phosphorylated state of STAT3 (Tyrr705Pho), decreasing the interaction of STAT3 with phosphatase enzymes such as the Protein Phosphatase 2A (PP2A), which interaction with STAT3 is enhanced with the pharmacological and genetic disruption of HDAC6. This study aims to understand the potential role of HDAC6 in the STAT3 activity and dimerization using a protein structural approach and molecular dynamics simulations. All structural data was obtained from the Protein Data Bank (PDB) (HDAC6 PDB ID: 5EDU and PP2A PDB ID: 2NPP), except for STAT3, which was obtained by protein homology modeling using SWISS-MODEL. The protein-protein interaction without post-translational modifications showed the high stability of the STAT3-HDAC6 and STAT3-PP2A protein complexes during the molecular dynamics simulation. Furthermore, the introduction of acetylation (Lys685Ac) and phosphorylation (Tyr705Pho) in STAT3 caused the instability of the protein complexes. The MM-PBSA binding free energy between HDAC6 and STAT3 showed the increment of binding between these proteins when STAT3 was only acetylated (−100.1 kcal/mol); on the other hand, in the STAT3-PP2A complex, there was an increase of the binding free energy when STAT3 was only phosphorylated (−67.1 kcal/mol). The selective and non-selective HDAC6 inhibitors showed that Suprastat could increase the STAT3-HDAC6 binding; however, Tubacin and Ricolinostat decreased the binding free energy between these two proteins. In the analysis of the STAT3 homodimerization, the simulation results showed the stability of the STAT3 dimers in the presence of 1 molecule of HDAC6. These results suggest the possible protective role of HDAC6 in the STAT3 activation and translocation to the nucleus favoring the STAT3 dimerization, enhancing the STAT3 activity. Therefore, the understanding of the STAT3-HDAC6 complex and its possible pharmacological disruption could be a potential target for developing new therapeutic strategies against diseases such as cancer.
Advisor: | Villagra, Alejandro, Hepp Castro, Matías Ignacio |
Commitee: | |
School: | The George Washington University |
Department: | Bioinformatics and Molecular Biochemistry |
School Location: | United States -- District of Columbia |
Source: | MAI 82/7(E), Masters Abstracts International |
Source Type: | DISSERTATION |
Subjects: | Bioinformatics, Biophysics, Biochemistry |
Keywords: | HDAC6, HDAC6 inhibitors, Molecular dynamics, PP2A, STAT3 |
Publication Number: | 28257381 |
ISBN: | 9798557083218 |