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In silico prediction of deleterious non-synonymous SNPs in STAT3

Athira Ajith
Athira Ajith
 et 
Usha Subbiah
Usha Subbiah
   | 18 oct. 2023
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Article Category: Original article
Publié en ligne: 18 oct. 2023
Pages: 185 - 199
DOI: https://doi.org/10.2478/abm-2023-0059
Mots clés
© 2023 Athira Ajith et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1.

Evolutionary conservancy of STAT3 by ConSurf server. The high-risk nsSNPs are denoted by black boxes. nsSNPs, non-synonymous single nucleotide polymorphisms; STAT, signal transducer and activator of transcription factors.
Evolutionary conservancy of STAT3 by ConSurf server. The high-risk nsSNPs are denoted by black boxes. nsSNPs, non-synonymous single nucleotide polymorphisms; STAT, signal transducer and activator of transcription factors.

Figure 2.

Structural variation of the wild-type and mutant residues by Project HOPE. The wild-type residue is presented as green and the mutant residue is shown in red.
Structural variation of the wild-type and mutant residues by Project HOPE. The wild-type residue is presented as green and the mutant residue is shown in red.

Figure 3.

Secondary structure prediction and calculations using SOPMA. The SOPMA program predicts the secondary structure of the STAT3 protein. The black boxes represent wild amino acids that might be altered by STAT3 pathogenic nsSNPs. Alpha helix, extended strand, beta turn, and random coil are all represented by the letters “h,” “e,” “t,” and “c,” respectively. nsSNPs, non-synonymous single nucleotide polymorphisms; STAT, signal transducer and activator of transcription factors.
Secondary structure prediction and calculations using SOPMA. The SOPMA program predicts the secondary structure of the STAT3 protein. The black boxes represent wild amino acids that might be altered by STAT3 pathogenic nsSNPs. Alpha helix, extended strand, beta turn, and random coil are all represented by the letters “h,” “e,” “t,” and “c,” respectively. nsSNPs, non-synonymous single nucleotide polymorphisms; STAT, signal transducer and activator of transcription factors.

Figure 4.

Protein–protein interaction network of STAT3 using STRING server showing strong functional association with EP300, PIAS3, IL10RA, JAK1, JAK2, EGFR, HSP90AA1, SRC, and homeobox protein NANOG. A weak interaction has been observed for HIF1A. EGFR, epidermal growth factor receptor; EP300, histone acetyltransferase p300; HIF1A, hypoxia-inducible factor 1-alpha; HSP90AA1, heat shock protein HSP 90-alpha; IL10RA, interleukin-10 receptor; JAK, Janus kinases; PIAS3, E3 SUMO-protein ligase; SRC, proto-oncogene tyrosine-protein kinase; STAT, signal transducer and activator of transcription factors; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.
Protein–protein interaction network of STAT3 using STRING server showing strong functional association with EP300, PIAS3, IL10RA, JAK1, JAK2, EGFR, HSP90AA1, SRC, and homeobox protein NANOG. A weak interaction has been observed for HIF1A. EGFR, epidermal growth factor receptor; EP300, histone acetyltransferase p300; HIF1A, hypoxia-inducible factor 1-alpha; HSP90AA1, heat shock protein HSP 90-alpha; IL10RA, interleukin-10 receptor; JAK, Janus kinases; PIAS3, E3 SUMO-protein ligase; SRC, proto-oncogene tyrosine-protein kinase; STAT, signal transducer and activator of transcription factors; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.

Figure 5.

3D model and binding site residues for domain 1 predicted by RaptorX.
3D model and binding site residues for domain 1 predicted by RaptorX.

Figure 6.

Gene–gene interaction network of STAT3 gene shows physical and genetic interaction with nuclear factor kappa B subunit 1 (NFKB1Z) and mitogen-activated protein kinase kinase 5 (MAP2K5), EGFR, and signal transducer and activator of transcription 1 (STAT1). EGFR, epidermal growth factor receptor; STAT, signal transducer and activator of transcription factors.
Gene–gene interaction network of STAT3 gene shows physical and genetic interaction with nuclear factor kappa B subunit 1 (NFKB1Z) and mitogen-activated protein kinase kinase 5 (MAP2K5), EGFR, and signal transducer and activator of transcription 1 (STAT1). EGFR, epidermal growth factor receptor; STAT, signal transducer and activator of transcription factors.

Figure 7.

3D structure prediction of STAT3 by AlphaFold. STAT, signal transducer and activator of transcription factors.
3D structure prediction of STAT3 by AlphaFold. STAT, signal transducer and activator of transcription factors.

Figure 8.

Visual representation of protein flexible conformation based on the vibrational entropy difference (ΔΔS) and the interatomic interaction between wild-type and mutant structures on STAT3 structure. Amino acids colored according to the vibrational entropy change upon mutation. BLUE represents a rigidification of the structure and RED a gain in flexibility. WT and MT residues are depicted as light-green sticks alongside the surrounding residues that are involved in any form of interaction.
Visual representation of protein flexible conformation based on the vibrational entropy difference (ΔΔS) and the interatomic interaction between wild-type and mutant structures on STAT3 structure. Amino acids colored according to the vibrational entropy change upon mutation. BLUE represents a rigidification of the structure and RED a gain in flexibility. WT and MT residues are depicted as light-green sticks alongside the surrounding residues that are involved in any form of interaction.

List of nsSNPs of STAT3 gene predicted as deleterious by different bioinformatics tools

S. No. rs ID Alleles Amino acid change SIFT (score) Polyphen (Humvar) (score) PANTHER SNP & GO (RI) PROVEAN (score) PHD -SNP (RI) MUTANT I DDG value (<0)
1 rs145786768 C/A V507F Deleterious (0.004) Probably damaging (0.990) Probably damaging Disease (9) Deleterious (−3.744) Disease (6) Decrease (−2.49)
2 rs193922716 G/A R335W Deleterious (0) Probably damaging (0.996) Probably damaging Disease (3) Deleterious (−5.816) Neutral (1) Decrease (−0.36)
3 rs193922717 C/T E415K Deleterious (0.003) Probably damaging (0.955) Probably damaging Disease (5) Deleterious (−3.097) Neutral (0) Decrease (−1.00)
4 rs193922719 T/A K591M Deleterious (0.002) Possibly damaging (0.751) Probably damaging Disease (8) Deleterious (−4.949) Disease (6) Decrease (−0.13)
5 rs1803125 G/T Q32K Deleterious (0.025) Possibly damaging (0.868) Probably damaging Disease (0) Neutral (−1.975) Disease (3) Decrease (−0.41)
6 rs11547455 G/A S629F Deleterious (0.001) Possibly damaging (0.481) Probably damaging Disease (5) Deleterious (−3.097) Disease (1) Increase (0.64)
7 rs11547455 G/A S727F Deleterious (0.002) Probably damaging (0.974) Probably damaging Neutral (0) Deleterious (−3.858) Neutral (1) Decrease (−0.20)
8 rs374063766 C/G Q198H Deleterious (0.035) Probably damaging (0.965) Probably damaging Neutral (3) Neutral (−1.942) Neutral (3) Decrease (−0.82)
9 rs11547455 G/A S727F Deleterious (0.002) Probably damaging (0.974) Probably damaging Neutral (0) Deleterious (−3.858) Neutral (1) Decrease (−0.20)

Analysis of evolutionary conservation profile of high-risk nsSNPs of STAT3 by ConSurf

Amino acid change Conservation score Buried/exposed Functional/structural
V507F 8 Buried -
R335W 9 Exposed Functional
E415K 8 Exposed -
K591M 9 Exposed Functional
F561Y 8 Exposed Functional
Q32K 7 Exposed -

Prediction of protein stability using DynaMut server

Amino acid change Stability-based prediction Δ Vibrational entropy energy
ΔΔG kcal/mol NMA-based predictions ΔΔG ENCoM Other structure-based predictions ΔΔSVib ENCoM (kcal/mol/K) Flexibility
ΔΔG mCSM (kcal/mol) DDG SDM (kcal/mol) ΔΔG DUET (kcal/mol)
Q32K 0.087 (Stabilizing) −0.009 kcal/mol (Destabilizing) −0.453 (Destabilizing) 0.030 (Stabilizing) −0.019 (Destabilizing) 0.012 Increase of molecule flexibility
F561Y −0.705 (Destabilizing) −0.089 (Destabilizing) −0.673 (Destabilizing) −1.030 (Destabilizing) −0.560 (Destabilizing) 0.111 Increase of molecule flexibility
K591M 0.057 (Stabilizing) 0.016 (Destabilizing) 0.335 (Stabilizing) 0.130 (Stabilizing) 0.485 (Stabilizing) −0.019 Decrease of molecule flexibility
E415K 0.107 (Stabilizing) 0.023 (Destabilizing) −0.461 (Destabilizing) −0.150 (Destabilizing) −0.062 (Destabilizing) −0.029 Decrease of molecule flexibility
V507F 0.627 (Stabilizing) 0.195 (Destabilizing) −1.244 (Destabilizing) −1.190 (Destabilizing) 1.458 (Destabilizing) −0.244 Decrease of molecule flexibility
R335W 0.050 (Stabilizing) −0.172 (Destabilizing) −0.198 (Destabilizing) −0.010 (Destabilizing) −0.447 (Destabilizing) 0.215 Increase of molecule flexibility

NetsurfP-2.0 prediction based on relative solvent accessibility, stability, and secondary structure prediction

Amino acid change NetsurfP-2.0
Class assignment RSA ASA Secondary structure Phi Psi
V507F Buried 13% 20 Å α helix −64° −44°
R335W Exposed 44% 101 Å Coil −110° 137°
E415K Exposed 52% 90 Å Strand/β sheet −108° 137°
K591M Exposed 37% 77 Å α helix −57° −41°
E594K Buried 6% 10 Å α helix −66° −41°
F561Y Buried 4% 8 Å α helix −60° −38°
R609S Buried 9% 22 Å Strand/β sheet −112° 132°
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