Molecular characterization of the archaic HLA-B∗73:01 allele reveals presentation of a unique peptidome and skewed engagement by KIR2DL2
Open accessPublished version of a preprint
Abstract
HLA class I alleles of archaic origin may have been retained in modern humans because they provide immunity against diseases to which archaic humans had evolved resistance. According to this model, archaic introgressed alleles were somehow distinct from those that evolved in African populations. Here we show that HLA-B*73:01, a rare allotype with putative archaic origins, has a relatively rare peptide binding motif with an unusually long-tailed peptide length distribution. We also find that HLA-B*73:01 combines a restricted and unique peptidome with high-cell surface expression, characteristics that make it well-suited to combat one or a number of closely-related pathogens. Furthermore, a crystal structure of HLA-B*73:01 in complex with KIR2DL2 highlights differences from previously solved structures with HLA-C molecules. These molecular characteristics distinguish HLA-B*73:01 from other HLA class I alleles previously investigated and may have provided early modern human migrants that inherited this allele with a selective advantage as they colonized Europe and Asia.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
The Strength of Selection against Neanderthal Introgression
Juric, I., Aeschbacher, S., & Coop, G. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1006340 · Cited by 309 · see citing works
Dannemann, M., Andrés, A. M., & Kelso, J. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.11.015 · Cited by 249 · see citing works
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- Authors
- Ross, P., Hilton, H. G., Lodwick, J., Slezak, T., Guethlein, L. A., McMurtrey, C. P., Han, A. S., Nielsen, M., Yong, D., Dulberger, C. L., Nolan, K. T., Roy, S., Castro, C. D., Hildebrand, W. H., Zhao, M., Kossiakoff, A., Parham, P., & Adams, E. J.
- Affiliations
- University of Chicago (US)
- Stanford Medicine (US)
- University of Oklahoma Health Sciences Center (US)
- Technical University of Denmark (DK)
- Corresponding author
- Parham, Peter
- Adams, Erin J.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2025-09
- Volume
- 301
- Issue
- 9
- Pages
- 110542
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC12450638
- OpenAlex
- W4412737771
- Cited by
- 1
- References
- 3
- Citations by year
- 2026: 1
- FWCI
- 0.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- University of Chicago (SCR_017760, SCR_019198)
- Argonne National Laboratory (DE-AC02-06CH11357)
- National Institutes of Health (R35GM143052, AI155984, AI17892, GM117372, AI22039)
- U.S. Department of Energy
- Office of Science
- Research Computing Center, University of Chicago
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- archaic introgression, HLA class I, peptide binding motifs, peptide length distribution, KIR2DL2, HLA-C, cell surface expression, pathogen resistance
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