Abstract
Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.
| Original language | English |
|---|---|
| Pages (from-to) | 387-394 |
| Number of pages | 8 |
| Journal | Nature Structural and Molecular Biology |
| Volume | 24 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2017 |
Keywords
- immunology
- x-ray crystallography
Cite this
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MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. / Pymm, Phillip; Illing, Patricia T; Ramarathinam, Sri H; O'Connor, Geraldine M.; Hughes, Victoria A; Hitchen, Corinne; Price, David A; Ho, Bosco K; McVicar, Daniel W; Brooks, Andrew G; Purcell, Anthony W; Rossjohn, Jamie; Vivian, Julian P.
In: Nature Structural and Molecular Biology, Vol. 24, No. 4, 04.2017, p. 387-394.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape
AU - Pymm, Phillip
AU - Illing, Patricia T
AU - Ramarathinam, Sri H
AU - O'Connor, Geraldine M.
AU - Hughes, Victoria A
AU - Hitchen, Corinne
AU - Price, David A
AU - Ho, Bosco K
AU - McVicar, Daniel W
AU - Brooks, Andrew G
AU - Purcell, Anthony W
AU - Rossjohn, Jamie
AU - Vivian, Julian P
PY - 2017/4
Y1 - 2017/4
N2 - Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.
AB - Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.
KW - immunology
KW - x-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=85013223117&partnerID=8YFLogxK
U2 - 10.1038/nsmb.3381
DO - 10.1038/nsmb.3381
M3 - Article
VL - 24
SP - 387
EP - 394
JO - Nature Structural Biology
JF - Nature Structural Biology
SN - 1545-9993
IS - 4
ER -