@article{fb38a8fbb47b44e18a13885e3350615b,
title = "Structural Basis of CD160:HVEM Recognition",
abstract = "CD160 is a signaling molecule that interacts with herpes virus entry mediator (HVEM) and contributes to a wide range of immune responses, including T cell inhibition, natural killer cell activation, and mucosal immunity. GPI-anchored and transmembrane isoforms of CD160 share the same ectodomain responsible for HVEM engagement, which leads to bidirectional signaling. Despite the importance of the CD160:HVEM signaling axis and its therapeutic relevance, the structural and mechanistic basis underlying CD160-HVEM engagement has not been described. We report the crystal structures of the human CD160 extracellular domain and its complex with human HVEM. CD160 adopts a unique variation of the immunoglobulin fold and exists as a monomer in solution. The CD160:HVEM assembly exhibits a 1:1 stoichiometry and a binding interface similar to that observed in the BTLA:HVEM complex. Our work reveals the chemical and physical determinants underlying CD160:HVEM recognition and initiation of associated signaling processes. Liu et al. determined the structures of human CD160 and its complex with HVEM, revealing the atomic basis for CD160:HVEM recognition. These structures highlight an intermolecular antiparallel β-sheet organization that supports the promiscuous binding properties of HVEM, enabling recognition of CD160, BTLA, and herpes simplex virus glycoprotein D.",
keywords = "CD160 and HVEM, IgSF and TNFRSF interactions, Interaction promiscuity, T cell costimulation and coinhibition, X-ray structures, immune regulation, intermolecular beta-sheet",
author = "Weifeng Liu and Garrett, {Sarah C.} and Fedorov, {Elena V.} and Ramagopal, {Udupi A.} and Garforth, {Scott J.} and Bonanno, {Jeffrey B.} and Almo, {Steven C.}",
note = "Funding Information: We thank the staff of X29A beamlines at the National Synchrotron Light Source. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-98CH10886. Financial support comes principally from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy (DOE), and from the National Center for Research Resources (P41RR012408) and the National Institute of General Medical Sciences (P41GM103473) of the National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US DOE Office of Science by Argonne National Laboratory, was supported by the US DOE under contract no. DE-AC02-06CH11357. Use of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline at Sector 31 of the Advanced Photon Source was provided by Eli Lilly Company, which operates the facility. We also acknowledge support from the Albert Einstein Cancer Center (P30CA013330), the Einstein Crystallographic Core X-ray Diffraction Facility supported by NIH Shared Instrumentation grant S10 OD020068 and the Albert Einstein Macromolecular Therapeutics Development Facility. This work was partially supported by the Price Family Foundation and contributions to the Albert Einstein Center for Experimental Therapeutics by Pamela and Edward S. Pantzer. We thank Dr. Mitchell Kronenberg for stimulating discussions. W.L. S.C.G. and S.C.A. designed the experiments. W.L. S.C.G. E.V.F. U.A.R. S.J.G. and J.B.B. conducted the experiments. W.L. S.J.G. and S.C.A. wrote the paper. S.C.A. supervised and administrated the project. The authors declare no competing interests. Funding Information: We thank the staff of X29A beamlines at the National Synchrotron Light Source. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the US Department of Energy, Office of Science , Office of Basic Energy Sciences , under contract no. DE-AC02-98CH10886. Financial support comes principally from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy (DOE), and from the National Center for Research Resources ( P41RR012408 ) and the National Institute of General Medical Sciences ( P41GM103473 ) of the National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US DOE Office of Science by Argonne National Laboratory, was supported by the US DOE under contract no. DE-AC02-06CH11357. Use of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline at Sector 31 of the Advanced Photon Source was provided by Eli Lilly Company, which operates the facility. We also acknowledge support from the Albert Einstein Cancer Center ( P30CA013330 ), the Einstein Crystallographic Core X-ray Diffraction Facility supported by NIH Shared Instrumentation grant S10 OD020068 and the Albert Einstein Macromolecular Therapeutics Development Facility. This work was partially supported by the Price Family Foundation and contributions to the Albert Einstein Center for Experimental Therapeutics by Pamela and Edward S. Pantzer. We thank Dr. Mitchell Kronenberg for stimulating discussions. Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = aug,
day = "6",
doi = "10.1016/j.str.2019.05.010",
language = "English (US)",
volume = "27",
pages = "1286--1295.e4",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "8",
}