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- Title
Structural and regulatory diversity shape HLA-C protein expression levels.
- Authors
Kaur, Gurman; Gras, Stephanie; Mobbs, Jesse I.; Vivian, Julian P.; Cortes, Adrian; Barber, Thomas; Kuttikkatte, Subita Balaram; Jensen, Lise Torp; Attfield, Kathrine E.; Dendrou, Calliope A.; Carrington, Mary; McVean, Gil; Purcell, Anthony W.; Rossjohn, Jamie; Fugger, Lars
- Abstract
Expression of HLA-C varies widely across individuals in an allele-specific manner. This variation in expression can influence efficacy of the immune response, as shown for infectious and autoimmune diseases. MicroRNA binding partially influences differential HLA-C expression, but the additional contributing factors have remained undetermined. Here we use functional and structural analyses to demonstrate that HLA-C expression is modulated not just at the RNA level, but also at the protein level. Specifically, we show that variation in exons 2 and 3, which encode the α1/α2 domains, drives differential expression of HLA-C allomorphs at the cell surface by influencing the structure of the peptide-binding cleft and the diversity of peptides bound by the HLA-C molecules. Together with a phylogenetic analysis, these results highlight the diversity and long-term balancing selection of regulatory factors that modulate HLA-C expression.
- Publication
Nature Communications, 2017, Vol 8, Issue 6, p15924
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/ncomms15924