PMID- 28218747 OWN - NLM STAT- MEDLINE DCOM- 20170619 LR - 20210225 IS - 1545-9985 (Electronic) IS - 1545-9993 (Print) IS - 1545-9985 (Linking) VI - 24 IP - 4 DP - 2017 Apr TI - MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. PG - 387-394 LID - 10.1038/nsmb.3381 [doi] 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. FAU - Pymm, Phillip AU - Pymm P AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. FAU - Illing, Patricia T AU - Illing PT AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. FAU - Ramarathinam, Sri H AU - Ramarathinam SH AUID- ORCID: 0000-0002-2787-1282 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. FAU - O'Connor, Geraldine M AU - O'Connor GM AD - Department of Biological Sciences, University of Chester, Chester, UK. FAU - Hughes, Victoria A AU - Hughes VA AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. FAU - Hitchen, Corinne AU - Hitchen C AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. FAU - Price, David A AU - Price DA AD - Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. AD - Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Ho, Bosco K AU - Ho BK AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. FAU - McVicar, Daniel W AU - McVicar DW AD - Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, Maryland, USA. FAU - Brooks, Andrew G AU - Brooks AG AD - Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia. FAU - Purcell, Anthony W AU - Purcell AW AUID- ORCID: 0000-0003-0532-8331 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. FAU - Rossjohn, Jamie AU - Rossjohn J AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. AD - Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. FAU - Vivian, Julian P AU - Vivian JP AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. LA - eng GR - WT_/Wellcome Trust/United Kingdom GR - Z01 BC010747-02/ImNIH/Intramural NIH HHS/United States GR - ZIA BC010747/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20170220 PL - United States TA - Nat Struct Mol Biol JT - Nature structural & molecular biology JID - 101186374 RN - 0 (Epitopes) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (KIR3DL1 protein, human) RN - 0 (Mutant Proteins) RN - 0 (Peptides) RN - 0 (Receptors, KIR3DL1) RN - 0 (gag Gene Products, Human Immunodeficiency Virus) SB - IM MH - Amino Acid Sequence MH - Crystallography, X-Ray MH - Epitopes/chemistry MH - HEK293 Cells MH - HIV-1/*metabolism MH - Histocompatibility Antigens Class I/*chemistry MH - Humans MH - *Immune Evasion MH - Metabolome MH - Mutant Proteins/chemistry MH - Mutation/genetics MH - Peptides/*chemistry/metabolism MH - Protein Binding MH - Protein Structure, Quaternary MH - Receptors, KIR3DL1/metabolism MH - Surface Plasmon Resonance MH - gag Gene Products, Human Immunodeficiency Virus/chemistry/metabolism PMC - PMC7900914 MID - NIHMS1665194 COIS- COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. EDAT- 2017/02/22 06:00 MHDA- 2017/06/20 06:00 PMCR- 2021/02/23 CRDT- 2017/02/21 06:00 PHST- 2015/08/16 00:00 [received] PHST- 2017/01/20 00:00 [accepted] PHST- 2017/02/22 06:00 [pubmed] PHST- 2017/06/20 06:00 [medline] PHST- 2017/02/21 06:00 [entrez] PHST- 2021/02/23 00:00 [pmc-release] AID - nsmb.3381 [pii] AID - 10.1038/nsmb.3381 [doi] PST - ppublish SO - Nat Struct Mol Biol. 2017 Apr;24(4):387-394. doi: 10.1038/nsmb.3381. Epub 2017 Feb 20.