The MHC-Ib Molecule HLA-F Presents Peptides and Regulates Immunity Through Interactions with NK-Cell Receptors /
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Author / Creator: | Dulberger, Charles Lefco, author. |
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Imprint: | 2017. Ann Arbor : ProQuest Dissertations & Theses, 2017 |
Description: | 1 electronic resource (111 pages) |
Language: | English |
Format: | E-Resource Dissertations |
Local Note: | School code: 0330 |
URL for this record: | http://pi.lib.uchicago.edu/1001/cat/bib/11715053 |
Other authors / contributors: | University of Chicago. degree granting institution. |
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ISBN: | 9780355077926 |
Notes: | Includes supplementary digital materials. Advisors: Erin J. Adams Committee members: Sean Crosson; Bana Jabri; Vincent J. Lynch. Dissertation Abstracts International, Volume: 78-12(E), Section: B. English |
Summary: | Evidence is mounting that HLA-F regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK-cell receptors (NKRs). We present structural, biochemical and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation in the antigen-binding cleft (R62W) that has produced an open-ended groove that accommodates particularly long peptides. Compared to empty HLA-F open conformers (OC), HLA-F tetramers bound with human-derived peptides differentially stain leukocytes suggesting peptide-dependent engagement. Our binding studies and functional assays confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F OC. The complex structure of peptide-loaded β 2m-HLA-F bound to the inhibitory LIR1 reveals similarities to high-affinity UL18 recognition and a docking strategy that relies on contacts with the HLA-F heavy chain as well as β2m, precluding binding to HLA-F OC. These findings provide the biochemical framework for how HLA-F regulates immunity via interactions with NKRs. Supplementary Table 2.2, which contains the peptide sequences eluted from HLA-F produced in HEK293T cells, can be found online. |
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