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Outline
To systematically analyze the polymorphic characteristics of the ITGA2 gene and the impact of the rs1126643 F253L mutation on the biological function of the ITGA2 protein and the antiplatelet effect of aspirin, thereby providing a theoretical foundation and potential genetic biomarkers for the individualized diagnosis and treatment of aspirin resistance (AR).
The ITGA2 gene and encoded protein sequences were obtained from NCBI and UniProt databases. Physicochemical properties and hydrophobicity profiles of the encoded protein were analyzed using ProtParam and Protscale, respectively. Protein-protein interaction networks were constructed via STRING, secondary structure elements were predicted using SOPMA and DNAStar, and tertiary structural models were generated using SWISS-MODEL, with detailed analysis of conformational differences at the mutation site. Functional and pathogenicity impacts of wild-type versus mutant proteins were assessed in silico, followed by validation through molecular docking and molecular dynamics simulations.
The ITGA2 gene spans 105 428 base pairs and encodes a 1 181 amino-acid protein, classifying it as an acidic, hydrophilic protein. Secondary structure analysis revealed that α-helices constitute 14.39%, extended strands 27.35%, and random coils 58.26% of the protein structure. Although the F253L substitution does not significantly alter the fundamental physicochemical properties of the protein, stability prediction tools including DUET and MUpro consistently indicated reduced structural stability. Six out of seven pathogenicity prediction algorithms classified the variant as highly pathogenic. MutPred2 analysis suggested that the mutation may disrupt protein function by decreasing relative solvent accessibility and altering ordered interfacial regions. The ITGA2 protein is involved in critical biological processes such as cell-matrix adhesion, and the F253L mutation may contribute to pathological mechanisms through structural and functional perturbations. These findings were further substantiated by molecular docking and molecular dynamics simulations.
The ITGA2 F253L mutation represents a core molecular mechanism underlying aspirin resistance, acting through destabilization of the ITGA2 protein structure, reduction in solvent accessibility, reduced binding affinity to aspirin, and thereby attenuating the antiplatelet effect of aspirin. This study highlights the pivotal role of the ITGA2 F253L polymorphism in modulating aspirin responsiveness and provides potential biomarkers and mechanistic insights for genetic profiling and personalized antiplatelet therapy in patients with AR.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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