TY - JOUR
T1 - From Rhesus macaque to human
T2 - structural evolutionary pathways for immunoglobulin G subclasses
AU - Tolbert, William David
AU - Subedi, Ganesh Prasad
AU - Gohain, Neelakshi
AU - Lewis, George Kenneth
AU - Patel, Kashyap Rajesh
AU - Barb, Adam Wesley
AU - Pazgier, Marzena
N1 - Funding Information:
We thank our IHV colleagues for outstanding support of the studies leading to the ideas presented above, specifically Dr. Krishanu Ray for his critical insights. This work was supported by NIH grants: NIAID R01 AI116274 and R01 AI129769 to MP, NIAID P01 AI120756 to GT, and NIGMS R01 GM115489 to AB. We thank Mr. Joel Nott of the ISU Protein Facility for assistance with the LC-ESI/MS/MS data collection, Dr. D. Bruce Fulton and Dr. Shu Xu (ISU) for help with NMR instrumentation. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The authors have no conflicts of interest to report.
Funding Information:
This work was supported by the National Institutes of Health [AI116274]; National Institutes of Health [GM115489]; National Institutes of Health [AI120756]; National Institutes of Health [AI129769].
Funding Information:
This work was supported by the National Institutes of Health [AI116274]; National Institutes of Health [GM115489]; National Institutes of Health [AI120756]; National Institutes of Health [AI129769]. We thank our IHV colleagues for outstanding support of the studies leading to the ideas presented above, specifically Dr. Krishanu Ray for his critical insights. This work was supported by NIH grants: NIAID R01 AI116274 and R01 AI129769 to MP, NIAID P01 AI120756 to GT, and NIGMS R01 GM115489 to AB. We thank Mr. Joel Nott of the ISU Protein Facility for assistance with the LC-ESI/MS/MS data collection, Dr. D. Bruce Fulton and Dr. Shu Xu (ISU) for help with NMR instrumentation. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The authors have no conflicts of interest to report.
Publisher Copyright:
© 2019, © 2019 Taylor & Francis Group, LLC.
PY - 2019/5/19
Y1 - 2019/5/19
N2 - The Old World monkey, Rhesus macaque (Macaca mulatta, Mm), is frequently used as a primate model organism in the study of human disease and to test new vaccines/antibody treatments despite diverging before chimpanzees and orangutans. Mm and humans share 93% genome identity with substantial differences in the genes of the adaptive immune system that lead to different functional IgG subclass characteristics, Fcγ receptors expressed on innate immune cells, and biological interactions. These differences put limitations on Mm use as a primary animal model in the study of human disease and to test new vaccines/antibody treatments. Here, we comprehensively analyzed molecular properties of the Fc domain of the four IgG subclasses of Rhesus macaque to describe potential mechanisms for their interactions with effector cell Fc receptors. Our studies revealed less diversity in the overall structure among the Mm IgG Fc, with MmIgG1 Fc being the most structurally like human IgG3, although its CH2 loops and N297 glycan mobility are comparable to human IgG1. Furthermore, the Fcs of Mm IgG3 and 4 lack the structural properties typical for their human orthologues that determine IgG3’s reduced interaction with the neonatal receptor and IgG4’s ability for Fab-arm exchange and its weaker Fcγ receptor interactions. Taken together, our data indicate that MmIgG1-4 are less structurally divergent than the human IgGs, with only MmIgG1 matching the molecular properties of human IgG1 and 3, the most active IgGs in terms of Fcγ receptor binding and Fc-mediated functions. PDB accession numbers for deposited structures are 6D4E, 6D4I, 6D4M, and 6D4N for MmIgG1 Fc, MmIgG2 Fc, MmIgG3 Fc, and MmIgG4 Fc, respectively.
AB - The Old World monkey, Rhesus macaque (Macaca mulatta, Mm), is frequently used as a primate model organism in the study of human disease and to test new vaccines/antibody treatments despite diverging before chimpanzees and orangutans. Mm and humans share 93% genome identity with substantial differences in the genes of the adaptive immune system that lead to different functional IgG subclass characteristics, Fcγ receptors expressed on innate immune cells, and biological interactions. These differences put limitations on Mm use as a primary animal model in the study of human disease and to test new vaccines/antibody treatments. Here, we comprehensively analyzed molecular properties of the Fc domain of the four IgG subclasses of Rhesus macaque to describe potential mechanisms for their interactions with effector cell Fc receptors. Our studies revealed less diversity in the overall structure among the Mm IgG Fc, with MmIgG1 Fc being the most structurally like human IgG3, although its CH2 loops and N297 glycan mobility are comparable to human IgG1. Furthermore, the Fcs of Mm IgG3 and 4 lack the structural properties typical for their human orthologues that determine IgG3’s reduced interaction with the neonatal receptor and IgG4’s ability for Fab-arm exchange and its weaker Fcγ receptor interactions. Taken together, our data indicate that MmIgG1-4 are less structurally divergent than the human IgGs, with only MmIgG1 matching the molecular properties of human IgG1 and 3, the most active IgGs in terms of Fcγ receptor binding and Fc-mediated functions. PDB accession numbers for deposited structures are 6D4E, 6D4I, 6D4M, and 6D4N for MmIgG1 Fc, MmIgG2 Fc, MmIgG3 Fc, and MmIgG4 Fc, respectively.
KW - Fc
KW - IgG subclasses
KW - Macaca mulatta
KW - Rhesus macaque
KW - crystallizable fragment
UR - http://www.scopus.com/inward/record.url?scp=85063767384&partnerID=8YFLogxK
U2 - 10.1080/19420862.2019.1589852
DO - 10.1080/19420862.2019.1589852
M3 - Article
C2 - 30939981
AN - SCOPUS:85063767384
SN - 1942-0862
VL - 11
SP - 709
EP - 724
JO - mAbs
JF - mAbs
IS - 4
ER -