Structural and regulatory diversity shape HLA-C protein expression levels

Gurman Kaur, Stephanie Gras, Jesse I. Mobbs, Julian P. Vivian, Adrian Cortes, Thomas Barber, Subita Balaram Kuttikkatte, Lise Torp Jensen, Kathrine E. Attfield, Calliope A. Dendrou, Mary Carrington, Gil McVean, Anthony W. Purcell, Jamie Rossjohn, Lars Fugger

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number15924
Number of pages12
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 26 Jun 2017

Keywords

  • antigen processing and presentation
  • immunogenetics
  • imunology
  • structural biology

Cite this

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. / Structural and regulatory diversity shape HLA-C protein expression levels. In: Nature Communications. 2017 ; Vol. 8.
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title = "Structural and regulatory diversity shape HLA-C protein expression levels",
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.",
keywords = "antigen processing and presentation, immunogenetics, imunology, structural biology",
author = "Gurman Kaur and Stephanie Gras and Mobbs, {Jesse I.} and Vivian, {Julian P.} and Adrian Cortes and Thomas Barber and Kuttikkatte, {Subita Balaram} and Jensen, {Lise Torp} and Attfield, {Kathrine E.} and Dendrou, {Calliope A.} and Mary Carrington and Gil McVean and Purcell, {Anthony W.} and Jamie Rossjohn and Lars Fugger",
year = "2017",
month = "6",
day = "26",
doi = "10.1038/ncomms15924",
language = "English",
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journal = "Nature Communications",
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Kaur, G, Gras, S, Mobbs, JI, Vivian, JP, Cortes, A, Barber, T, Kuttikkatte, SB, Jensen, LT, Attfield, KE, Dendrou, CA, Carrington, M, McVean, G, Purcell, AW, Rossjohn, J & Fugger, L 2017, 'Structural and regulatory diversity shape HLA-C protein expression levels' Nature Communications, vol. 8, 15924. https://doi.org/10.1038/ncomms15924

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, 15924, 26.06.2017.

Research output: Contribution to journalArticleResearchpeer-review

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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

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