Abstract Number: PB0894
Meeting: ISTH 2021 Congress
Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Platelet Function Disorders, Hereditary
Background: We described a novel disease-causing variant (DCV) p.Tyr231Cys in the GP1BA gene related to recessive BSS in a patient with no bleeding symptoms and 50% CD42b-expression. Homology modelling was used to describe the effects of this DCV on protein-protein interaction.
Aims: To study effect of the GPIbα-p.Tyr231Cys on the interaction of GPIbα with VWF-A1 domain by homology modelling.
Methods: The model GPIbα-p.Tyr231Cys was made by replacing Tyr231 by Cys in wild-type-GPIbα (Swiss-PDBviewer). Docking between VWF-A1 and GPIbα-p.Tyr231Cys was obtained (PatchDock) and compared to WT-GPIbα-VWF-A1. Hydrogen-bonds and root-mean-square deviation (RMSD) between α-carbon chains were obtained (UCSF Chimera).
Results: GPIbα-Tyr231 is found in the a2-helix, nearby two disulphide-bonds: C225-C264; C227-C280. No new disulphide-bonds are predicted in GPIbα-p.Tyr231Cys. GPIbα-Tyr231 forms intramolecular hydrogen-bonds with Phe208, Trp235 and Glu228.In p.Cys231Tyr, hydrogen-bond with Phe208 is lost and a new bond is formed with Ile203. The bond with Trp235 is maintained and is still present with Glu228 but at a larger distance, consequently, weaker.
In silico-model of wild-type-GPIbα-VWF-A1 (Fig-1A) shows differences with GPIbα-p.Tyr231Cys-VWF-A1(Fig-1B). Total RMSD between models is 38.05Å (0.65Å between GPIbα portions; 15.07Å between VWF-A1 domains) (Fig-1C). The change Tyr231Cys causes a slight alteration in the conformation of GPIba (0.65Å) respecting wild-type-GPIbα. This change does not affect neighboring residues but alters the structure of GPIbα at the site that acts as a hinge, increasing the distance of the b-switch region of GPIba (flexible loop at Val243-Ser257). This modifies the interaction with VWF-A1, changing hydrogen-bonds between these molecules (Table 1).
Hypothetical model of GPIba with the A1 domain of VWF. A) A1 (cian) with wild-type GPIba (magenta); B) A1 (orange) with mutated GPIba-p.Tyr231Cys; C) overlap of both models
| Wild-type-GPIba | Residue on GPIba | Residue on VWF-A1 domain | H-bond Distance/Å |
| Lys253 | Ala1327 | 3.0 | |
| 3.2 | |||
| Met255 | Ser1325 | 3.0 | |
| 2.9 | |||
| GPIba-Tyr231Cys | Gln143 | Lys1371 | 1.7 |
| Ile1368 | 3.6 | ||
| Glu241 | His1322 | 3.2 | |
| Asp251 | Arg1336 | 3.4 | |
| Ser1338 | 3.2 |
Predicted hydrogen-bonds distance between wild-type-GPIba and the VWF-A1 domain and between GPIba-p.Tyr231Cys and the VWF-A1 domain
Conclusions: In-silico predictions show that GP1BA-p.Tyr231Cys modifies the tertiary structure of GPIba affecting the interaction with VWF-A1, explaining its negative effect that influences in both platelet count and size and in 50% expression of GPIb as observed in our patient. The change Tyr231Cys could be preventing the conformational change of the b-switch from compact to extended thus altering the VWF-GPIbα binding.
To cite this abstract in AMA style:
M Primrose D, Woods AI, F Alberto M, Paiva J, Asencio M, M Casinelli M, N Blanco A, Sánchez-Luceros A. Modelling Studies to Characterize a Novel Disease-causing Variant in the GP1BA Gene Related to Bernard Soulier Syndrome [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/modelling-studies-to-characterize-a-novel-disease-causing-variant-in-the-gp1ba-gene-related-to-bernard-soulier-syndrome/. Accessed June 25, 2022.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/modelling-studies-to-characterize-a-novel-disease-causing-variant-in-the-gp1ba-gene-related-to-bernard-soulier-syndrome/