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. 2014:2014:904052.
doi: 10.1155/2014/904052. Epub 2014 Mar 4.

First comprehensive in silico analysis of the functional and structural consequences of SNPs in human GalNAc-T1 gene

Hussein Sheikh Ali Mohamoud  1 , Muhammad Ramzan Manwar Hussain  2 , Ashraf A El-Harouni  3 , Noor Ahmad Shaik  3 , Zaheer Ulhaq Qasmi  4 , Amir Feisal Merican  5 , Mukhtiar Baig  6 , Yasir Anwar  7 , Hani Asfour  2 , Nabeel Bondagji  2 , Jumana Yousuf Al-Aama  3
Affiliations

First comprehensive in silico analysis of the functional and structural consequences of SNPs in human GalNAc-T1 gene

Hussein Sheikh Ali Mohamoud et al. Comput Math Methods Med. 2014.

Abstract

GalNAc-T1, a key candidate of GalNac-transferases genes family that is involved in mucin-type O-linked glycosylation pathway, is expressed in most biological tissues and cell types. Despite the reported association of GalNAc-T1 gene mutations with human disease susceptibility, the comprehensive computational analysis of coding, noncoding and regulatory SNPs, and their functional impacts on protein level, still remains unknown. Therefore, sequence- and structure-based computational tools were employed to screen the entire listed coding SNPs of GalNAc-T1 gene in order to identify and characterize them. Our concordant in silico analysis by SIFT, PolyPhen-2, PANTHER-cSNP, and SNPeffect tools, identified the potential nsSNPs (S143P, G258V, and Y414D variants) from 18 nsSNPs of GalNAc-T1. Additionally, 2 regulatory SNPs (rs72964406 and #x26; rs34304568) were also identified in GalNAc-T1 by using FastSNP tool. Using multiple computational approaches, we have systematically classified the functional mutations in regulatory and coding regions that can modify expression and function of GalNAc-T1 enzyme. These genetic variants can further assist in better understanding the wide range of disease susceptibility associated with the mucin-based cell signalling and pathogenic binding, and may help to develop novel therapeutic elements for associated diseases.

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Figures

Figure 1
Figure 1
Schematic representation of computational tools for in silico analysis of GalNAc-T1 gene.
Figure 2
Figure 2
Superimposed structures of GalNAc-T1 native (camel color) and mutant (blue color) models to visualize the stereochemical conformation of wild type and mutant residues at 143, 258, and 414 positions.
Figure 3
Figure 3
H-bonding (green discontinuous line) interactions and clashes (pink discontinuous line) of wild type and mutant analogues with the vicinal amino acid residues. (a) Ser143 is examined with single H-bonding with Val139 and converted into clash as a result of Pro at the same position. (b) At 258 position, one H-bond is observed with Arg266 in both native (Gly258) and mutant (Val258) structures, but a network of clashes appeared between Val258 and Tyr268. (c) Tyr414 is visualized with five H-bonding interactions for Pro410 and Asn417, and one H-bond is distorted due to appearance of mutant aspartic acid at the same position.
Figure 4
Figure 4
Multiple sequence alignments and evolutionary conservation behaviour among human GalNAc-T1 to GalNAc-T10 members of GALNTs family. S143 and Y414 residues are found conserved in the catalytic subdomain A and linker B domain (area between catalytic subdomain B and Ricin B-type lectin), respectively. G258 is observed in the vicinity of conservation groups with strongly similar properties (shown with “:”).
Figure 5
Figure 5
GalNAc-T1 protein-protein interactions with 09 partners. One colour is given to each type of evidence in the predicted functional links (edges) among eight coloured lines. (a) From experimental basis (with score 0.925), only MUC1 is observed for interaction with GalNAc-T1. From text-mining data, GalNAc-T1 interactions are observed for GBGT1, CHPF, ST6GALNAC1, B4GALNT1, and MUC1 proteins with 0.970, 0.968, 0.952, 0.926, and 0.925 scores, respectively. The remaining interactions with C1GALT1C1, CIGALT1, GCNT1, and B3GNT6 proteins are simulated with STRING score ranging from 0.900 to 0.899. (b) Strong association pattern (thick blue lines) of GalNAc-T1 is predicted for GBGT1, CHPF, ST6GALNAC1, B4GALNT1, MUC1, C1GALT1C1, C1GALT1, GCNT1, B3GNT6, and ZNF146 partners with high confidence. For ST6GALNAC1-GBGT1, ST6GALNAC1-MUC1, GCNT1-CHPF, B4GALNT1-GCNT1, CHPF-C1GALT1C1, and GALNT1-ZNF146 pairs, weak associations are examined in the form of thin blue lines.
Figure 6
Figure 6
3D visualization of G258V variant with MUC1. (a) Ligand binding of GalNAc-T1 native structure with MUC1 indicated single H-bonding interaction (green line) of Gly258 residue (green portion) with Arg266 which is further connected with the GVTSA (tandem repeat region of MUC1) by means of H-bonding interaction. (b) Picturing of GalNAc-T1 mutant protein structure is observed with one H-bonding loss between Arg266 residue and the MUC1 tandem repeat motif.
Figure 7
Figure 7
Complex structure of GalNAc-T1 enzyme with UDP, MUC1 (tandem repeat region “GSTAPPAHGVTSAP”), and GalNAc residue. GalNAc sugar is attached at Thr of tandem repeat region in MUC1. His125 and Asp156 residues from catalytic A domain and Ile315, Trp316, and Thr350 from catalytic B domain are found in contact with UDP (orange red color). Under the action of ST6GALNAC1, B4GALNT1, C1GALT1C1, C1GALT1, GCNT1, and B3GNT6, GalNAc1-O-Thr is stereospecifically converted into different glycan chains to regulate the mucin biosynthesis pathway.
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