Abstract
Measles virus (MV) is a human pathogen that is classified in the genus Morbillivirus in the family Paramyxoviridae together with several non-human animal morbilliviruses. They cause severe systemic infections by using signaling lymphocytic activation molecule (SLAM) and poliovirus receptor-like 4 expressed on immune and epithelial cells, respectively, as receptors. The viral hemagglutinin (H) protein is responsible for the receptor-binding. Previously determined structures of MV-H and SLAM complexes revealed a major binding interface between the SLAM V domain and MV-H with four binding components (sites 1–4) in the interface. We studied the MV-H and human SLAM (hSLAM) complex structure in further detail by in silico analyses and determined missing regions or residues in the previously determined complex structures. These analyses showed that, in addition to sites 1–4, MV-H establishes a unique interaction with the extreme N-terminal region (ExNTR) of hSLAM. The first principles calculation-based fragment molecular orbital computation method revealed that methionine at position 29 (hSLAM-Met29) is the key residue for the interaction. hSLAM-Met29 was predicted to establish a CH-π interaction with phenylalanine at position 549 of MV-H (MVH-Phe549). A cell-cell fusion assay showed that the hSLAM-Met29 and MVH-Phe549 interaction is important for hSLAM-dependent MV membrane fusion. Furthermore, Jurkat cell lines expressing hSLAM with or without Met29 and recombinant MV possessing the H protein with or without Phe549 showed that the hSLAM-Met29 and MVH-Phe549 interaction enhanced hSLAM-dependent MV infection by ~10-fold. We speculate that in the evolutionary history of morbilliviruses, this interaction may have contributed to MV adaptation to humans because this interaction is unique for MV and only MV uses hSLAM efficiently among morbilliviruses.
Highlights
Despite the availability of highly effective vaccines, measles remains a major cause of human mortality and morbidity
Chinese hamster ovarian (CHO)/DSP1–7 and CHO/DSP8–11 cells were generated by transfecting CHO cells with pRL-DSP1–7-neo and pRL-DSP8–11-neo, respectively, and were selected in Roswell Park Memorial Institute (RPMI) medium supplemented with 7% fetal bovine serum (FBS) and 0.5 mg/ml geneticin
The data showed that, in addition to the four binding components between signaling lymphocytic activation molecule (SLAM) and Measles virus (MV)-H, which were identified previously (Hashiguchi et al, 2011), the extreme N-terminal region (ExNTR) of human SLAM (hSLAM) formed an effective interaction with MV H protein (MV-H) (Figures 2B,C)
Summary
Despite the availability of highly effective vaccines, measles remains a major cause of human mortality and morbidity. Crystal structure data (Hashiguchi et al, 2011) show four binding components (sites 1–4) between SLAM and Abbreviations: MV, Measles virus; SLAM, Signaling lymphocytic activation molecule; PVRL4, Poliovirus receptor-like 4; H, Hemagglutinin; F, Fusion; RPV, Rinderpest virus; PPRV, Peste des petits ruminants virus; CeMV, Cetacean morbillivirus; PDV, Phocine distemper virus; CDV, Canine distemper virus; hSLAM, Human SLAM; MV-H, MV H protein; ExNTR, Extreme N-terminal region; DMEM, Dulbecco’s modified Eagle’s medium; FBS, Fetal bovine serum; DSP, Dual split protein; EGFP, Enhanced green fluorescent protein; PBS, Phosphatebuffered saline; PI, Post-infection; PFU, Plaque forming unit; CIU, Cell infectious unit; MOE, Molecular Operating Environment; MD, Molecular dynamics; MM-GB/ SA, Molecular mechanics generalized Born surface area; FMO, Fragment molecular orbital; RI-MP2, Resolution-of-identity second-order Moller Plesset; IFIEs, Interfragment interaction energies
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