TY - JOUR
T1 - Distinct dissociation rates of murine and human norovirus P-domain dimers suggest a role of dimer stability in virus-host interactions
AU - Creutznacher, Robert
AU - Maass, Thorben
AU - Dülfer, Jasmin
AU - Feldmann, Clara
AU - Hartmann, Veronika
AU - Lane, Miranda Sophie
AU - Knickmann, Jan
AU - Westermann, Leon Torben
AU - Thiede, Lars
AU - Smith, Thomas J.
AU - Uetrecht, Charlotte
AU - Mallagaray, Alvaro
AU - Waudby, Christopher A.
AU - Taube, Stefan
AU - Peters, Thomas
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/9
Y1 - 2022/6/9
N2 - Norovirus capsids are icosahedral particles composed of 90 dimers of the major capsid protein VP1. The C-terminus of the VP1 proteins forms a protruding (P)-domain, mediating receptor attachment, and providing a target for neutralizing antibodies. NMR and native mass spectrometry directly detect P-domain monomers in solution for murine (MNV) but not for human norovirus (HuNoV). We report that the binding of glycochenodeoxycholic acid (GCDCA) stabilizes MNV-1 P-domain dimers (P-dimers) and induces long-range NMR chemical shift perturbations (CSPs) within loops involved in antibody and receptor binding, likely reflecting corresponding conformational changes. Global line shape analysis of monomer and dimer cross-peaks in concentration-dependent methyl TROSY NMR spectra yields a dissociation rate constant koff of about 1 s−1 for MNV-1 P-dimers. For structurally closely related HuNoV GII.4 Saga P-dimers a value of about 10−6s−1 is obtained from ion-exchange chromatography, suggesting essential differences in the role of GCDCA as a cofactor for MNV and HuNoV infection.
AB - Norovirus capsids are icosahedral particles composed of 90 dimers of the major capsid protein VP1. The C-terminus of the VP1 proteins forms a protruding (P)-domain, mediating receptor attachment, and providing a target for neutralizing antibodies. NMR and native mass spectrometry directly detect P-domain monomers in solution for murine (MNV) but not for human norovirus (HuNoV). We report that the binding of glycochenodeoxycholic acid (GCDCA) stabilizes MNV-1 P-domain dimers (P-dimers) and induces long-range NMR chemical shift perturbations (CSPs) within loops involved in antibody and receptor binding, likely reflecting corresponding conformational changes. Global line shape analysis of monomer and dimer cross-peaks in concentration-dependent methyl TROSY NMR spectra yields a dissociation rate constant koff of about 1 s−1 for MNV-1 P-dimers. For structurally closely related HuNoV GII.4 Saga P-dimers a value of about 10−6s−1 is obtained from ion-exchange chromatography, suggesting essential differences in the role of GCDCA as a cofactor for MNV and HuNoV infection.
UR - http://www.scopus.com/inward/record.url?scp=85131707457&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/23f9d614-eaa0-300c-a839-6b6050942a21/
U2 - 10.1038/s42003-022-03497-4
DO - 10.1038/s42003-022-03497-4
M3 - Journal articles
C2 - 35680964
AN - SCOPUS:85131707457
SN - 2399-3642
VL - 5
SP - 563
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 563
ER -
