Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
Structural and regulatory diversity shape HLA-C protein expression levels. / 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.
In: Nature Communications, Vol. 8, 26.06.2017, p. 15924.Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural and regulatory diversity shape HLA-C protein expression levels
AU - Kaur, Gurman
AU - Gras, Stephanie
AU - Mobbs, Jesse I
AU - Vivian, Julian P
AU - Cortes, Adrian
AU - Barber, Thomas
AU - Kuttikkatte, Subita Balaram
AU - Jensen, Lise Torp
AU - Attfield, Kathrine E
AU - Dendrou, Calliope A
AU - Carrington, Mary
AU - McVean, Gil
AU - Purcell, Anthony W
AU - Rossjohn, Jamie
AU - Fugger, Lars
PY - 2017/6/26
Y1 - 2017/6/26
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1038/ncomms15924
DO - 10.1038/ncomms15924
M3 - Journal article
C2 - 28649982
VL - 8
SP - 15924
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
ER -