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Insights into anti‐D formation in carriers of RhD variants through studies of 3D intraprotein interactions

Abstract : Background: Many RhD variants associated with anti-D formation (partial D) in carriers exposed to the conventional D antigen carry mutations affecting extracellular loop residues. Surprisingly, some carry mutations affecting transmembrane or intracellular domains, positions not thought likely to have a major impact on D epitopes. Study design and methods: A wild-type Rh trimer (RhD1 RhAG2 ) was modeled by comparative modeling with the human RhCG structure. Taking trimer conformation, residue accessibility, and position relative to the lipid bilayer into account, we redefine the domains of the RhD protein. We generated models for RhD variants carrying one or two amino acid substitutions associated with anti-D formation in published articles (25 variants) or abstracts (12 variants) and for RHD*weak D type 38. We determined the extracellular substitutions and compared the interactions of the variants with those of the standard RhD. Results: The findings of the three-dimensional (3D) analysis were correlated with anti-D formation for 76% of RhD variants: 15 substitutions associated with anti-D formation concerned extracellular residues, and structural differences in intraprotein interactions relative to standard RhD were observed in the others. We discuss the mechanisms by which D epitopes may be modified in variants in which the extracellular residues are identical to those of standard RhD and provide arguments for the benignity of p.T379M (RHD*DAU0) and p.G278D (RHD*weak D type 38) in transfusion medicine. Conclusion: The study of RhD intraprotein interactions and the precise redefinition of residue accessibility provide insight into the mechanisms through which RhD point mutations may lead to anti-D formation in carriers.
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https://www.hal.inserm.fr/inserm-03253510
Contributor : Christophe Tournamille <>
Submitted on : Tuesday, June 8, 2021 - 12:29:35 PM
Last modification on : Thursday, September 16, 2021 - 10:44:08 AM
Long-term archiving on: : Thursday, September 9, 2021 - 7:00:31 PM

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Aline Floch, France Pirenne, Aurélie Barrault, Btissam Chami, Cécile Toly‐ndour, et al.. Insights into anti‐D formation in carriers of RhD variants through studies of 3D intraprotein interactions. Transfusion, Wiley, 2021, 61 (4), pp.1286-1301. ⟨10.1111/trf.16301⟩. ⟨inserm-03253510⟩

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