Global Shape and Ligand Binding Efficiency of the HIV-1-neutralizing Antibodies Differ from Those of Antibodies That Cannot Neutralize HIV-1
Abstract
Asymmetric disposition of Fab arms in the structures solved for the broadly neutralizing monoclonal antibody (nmAb) IgG1 b12 raised the question of whether the unusual shape observed for b12 is common for all IgG1 mAbs or if there is a difference in the overall shape of nmAbs versus non-nmAbs. In this paper, we compared small angle x-ray scattering (SAXS) data-based models and limited proteolysis profiles of some IgG1 mAbs known to be having and lacking HIV-1 neutralizing potency. In non-nmAbs, the Fab arms were found to be symmetrically disposed in space relative to central Fc, but in most nmAbs, the Fab arms were asymmetrically disposed, as seen for IgG1 b12. The only exceptions were 2G12 and 4E10, where both Fab arms were closed above Fc, suggesting some Fab-Fc and/or Fab-Fab interaction in the nmAbs that constrained extension of the Fab-Fc linker. Interestingly, these observations were correlated with differential proteolysis profiles of the mAbs by papain. Under conditions when papain could cut both Fab arms of non-nmAbs, only one Fab arm could be removed from neutralizing ones (except for 2G12 and 4E10). Chromatography and small angle x-ray scattering results of papain-digested products revealed that 1) the Fab-Fc or Fab-Fab interactions inmore »
- Authors:
-
- CSIR-Inst. of Microbial Technology, Chandigarh (India)
- Univ. of Pennsylvania, Philadelphia, PA (United States)
- Publication Date:
- Research Org.:
- Univ. of Pennsylvania, Philadelphia, PA (United States); CSIR-Inst. of Microbial Technology, Chandigarh (India)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1349034
- Grant/Contract Number:
- AC02-98CH10886
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 289; Journal Issue: 50; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; HIV-1 Protease; Molecular Modeling; Protein Folding; Protein Structure; X-ray Scattering; Global Shape; Limited Proteolysis; Neutralizing Antibodies; Small Angle X-ray Scattering; Solution Scattering
Citation Formats
Solanki, Ashish K., Rathore, Yogendra S., Badmalia, Maulik D., Dhoke, Reema R., Nath, Samir K., and Nihalani, Deepak. Global Shape and Ligand Binding Efficiency of the HIV-1-neutralizing Antibodies Differ from Those of Antibodies That Cannot Neutralize HIV-1. United States: N. p., 2014.
Web. doi:10.1074/jbc.M114.563486.
Solanki, Ashish K., Rathore, Yogendra S., Badmalia, Maulik D., Dhoke, Reema R., Nath, Samir K., & Nihalani, Deepak. Global Shape and Ligand Binding Efficiency of the HIV-1-neutralizing Antibodies Differ from Those of Antibodies That Cannot Neutralize HIV-1. United States. https://doi.org/10.1074/jbc.M114.563486
Solanki, Ashish K., Rathore, Yogendra S., Badmalia, Maulik D., Dhoke, Reema R., Nath, Samir K., and Nihalani, Deepak. Mon .
"Global Shape and Ligand Binding Efficiency of the HIV-1-neutralizing Antibodies Differ from Those of Antibodies That Cannot Neutralize HIV-1". United States. https://doi.org/10.1074/jbc.M114.563486. https://www.osti.gov/servlets/purl/1349034.
@article{osti_1349034,
title = {Global Shape and Ligand Binding Efficiency of the HIV-1-neutralizing Antibodies Differ from Those of Antibodies That Cannot Neutralize HIV-1},
author = {Solanki, Ashish K. and Rathore, Yogendra S. and Badmalia, Maulik D. and Dhoke, Reema R. and Nath, Samir K. and Nihalani, Deepak},
abstractNote = {Asymmetric disposition of Fab arms in the structures solved for the broadly neutralizing monoclonal antibody (nmAb) IgG1 b12 raised the question of whether the unusual shape observed for b12 is common for all IgG1 mAbs or if there is a difference in the overall shape of nmAbs versus non-nmAbs. In this paper, we compared small angle x-ray scattering (SAXS) data-based models and limited proteolysis profiles of some IgG1 mAbs known to be having and lacking HIV-1 neutralizing potency. In non-nmAbs, the Fab arms were found to be symmetrically disposed in space relative to central Fc, but in most nmAbs, the Fab arms were asymmetrically disposed, as seen for IgG1 b12. The only exceptions were 2G12 and 4E10, where both Fab arms were closed above Fc, suggesting some Fab-Fc and/or Fab-Fab interaction in the nmAbs that constrained extension of the Fab-Fc linker. Interestingly, these observations were correlated with differential proteolysis profiles of the mAbs by papain. Under conditions when papain could cut both Fab arms of non-nmAbs, only one Fab arm could be removed from neutralizing ones (except for 2G12 and 4E10). Chromatography and small angle x-ray scattering results of papain-digested products revealed that 1) the Fab-Fc or Fab-Fab interactions in unliganded mAbs are retained in digested products, and 2) whereas anti-gp120 non-nmAbs could bind two gp120 molecules, nmAbs could bind only one gp120. Finally, additional experiments showed that except for 2G12 and 4E10, unopen shapes of nmAbs remain uninfluenced by ionic strength but can be reversibly opened by low pH of buffer accompanied by loss of ligand binding ability.},
doi = {10.1074/jbc.M114.563486},
journal = {Journal of Biological Chemistry},
number = 50,
volume = 289,
place = {United States},
year = {Mon Oct 20 00:00:00 EDT 2014},
month = {Mon Oct 20 00:00:00 EDT 2014}
}
Web of Science
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