Rxivist logo

Structure of human cytomegalovirus UL144, an HVEM orthologue, bound to the B and T cell Lymphocyte Attenuator

By Aruna Bitra, Ivana Nemčovičová, Gaelle Picarda, Tzanko Doukov, Jing Wang, Chris A Benedict, Dirk M Zajonc

Posted 29 Mar 2019
bioRxiv DOI: 10.1101/591883 (published DOI: 10.1074/jbc.RA119.009199)

Human cytomegalovirus (HCMV) is a β-herpesvirus that has co-evolved with the host immune system to establish lifelong persistence. HCMV encodes many immune-modulatory molecules, including the glycoprotein UL144. UL144 is a structural mimic of the TNFRSF member HVEM, which binds to various ligands LIGHT, LTα, BTLA, CD160 and gD. However, in contrast to HVEM, UL144 selectively binds to only BTLA, inhibiting T cell activation. Here, we report the crystal structure of the UL144/BTLA complex, providing key insights into the molecular mechanisms underlying this virus-host protein interaction. Our structure reveals that UL144 utilizes residues from its N-terminal CRD1 to interact with BTLA in an orientation similar, but not exactly, to that of HVEM. The structural modifications at the CRD1 region of UL144 compared to HVEM have a significant impact on the fine-tuning of BTLA-binding. In addition, the N-terminal CRD2 loop of UL144 is shorter compared to the corresponding region of HVEM, altering the relative orientation of CRD2 with respect to CRD1. Employing structure-guided mutagenesis we have identified a mutant of BTLA (L123A) that interferes with binding to HVEM while preserving interaction towards UL144. Furthermore, our results illuminate structural differences between UL144 and HVEM that explain the inability of UL144 to bind to either LIGHT or CD160. In summary, the specific molecular differences that UL144 has evolved to exclusively target BTLA highlight it as a suitable scaffold for designing superior BTLA agonists that have high potential for potently inhibiting immune responses.

Download data

  • Downloaded 282 times
  • Download rankings, all-time:
    • Site-wide: 125,767
    • In immunology: 3,798
  • Year to date:
    • Site-wide: 116,444
  • Since beginning of last month:
    • Site-wide: 103,292

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

News