Global structures of IgG isotypes expressing identical variable regions

Ertan Eryilmaz; Alena Janda; Jungwook Kim; Radames J.B. Cordero; David Cowburn; Arturo Casadevall

doi:10.1016/j.molimm.2013.06.006

Global structures of IgG isotypes expressing identical variable regions

Ertan Eryilmaz, Alena Janda, Jungwook Kim, Radames J.B. Cordero, David Cowburn, Arturo Casadevall

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Until relatively recently the immunoglobulin molecule was viewed as composed of two independent domains comprised of the variable (V) and constant (C) regions. However, recent work has established that the C region mediates allosteric changes in the V region that can influence specificity and affinity. To further explore cross-domain interrelationship in murine IgG structure we carried out solution small angle X-ray scattering (SAXS) measurements for four V region identical IgG isotypes. SAXS analysis revealed elongated Y-shaped structures in solution with significantly different, isotype-dependent domain orientations. To further explore local C region effects on the V region, the IgG₃ Fab crystal structure from the same family was determined to 2.45Å resolution. The IgG₃ Fab crystal structure differs from a closely related previously solved IgG₁ Fab revealing significant structural differences, which may account for isotype-related specificity differences in V region identical Abs. Among the four murine isotypes, IgG₃ was the most different in solution with regards to overall structure as well as aggregate formation in solution suggesting that the greater apparent affinity of this isotype resulted from polyvalent complexes with enhanced avidity. Our results provide additional evidence that Ig V and C domains influence each other structurally and suggest that V region structure can have significant effects on overall Ig structure.

Original language	English (US)
Pages (from-to)	588-598
Number of pages	11
Journal	Molecular Immunology
Volume	56
Issue number	4
DOIs	https://doi.org/10.1016/j.molimm.2013.06.006
State	Published - Dec 31 2013

Keywords

Antigen
Constant domain
Immunoglobulin
Isotype
SAXS
Variable domain
X-ray crystallography

ASJC Scopus subject areas

Immunology
Molecular Biology

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10.1016/j.molimm.2013.06.006

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title = "Global structures of IgG isotypes expressing identical variable regions",

abstract = "Until relatively recently the immunoglobulin molecule was viewed as composed of two independent domains comprised of the variable (V) and constant (C) regions. However, recent work has established that the C region mediates allosteric changes in the V region that can influence specificity and affinity. To further explore cross-domain interrelationship in murine IgG structure we carried out solution small angle X-ray scattering (SAXS) measurements for four V region identical IgG isotypes. SAXS analysis revealed elongated Y-shaped structures in solution with significantly different, isotype-dependent domain orientations. To further explore local C region effects on the V region, the IgG3 Fab crystal structure from the same family was determined to 2.45{\AA} resolution. The IgG3 Fab crystal structure differs from a closely related previously solved IgG1 Fab revealing significant structural differences, which may account for isotype-related specificity differences in V region identical Abs. Among the four murine isotypes, IgG3 was the most different in solution with regards to overall structure as well as aggregate formation in solution suggesting that the greater apparent affinity of this isotype resulted from polyvalent complexes with enhanced avidity. Our results provide additional evidence that Ig V and C domains influence each other structurally and suggest that V region structure can have significant effects on overall Ig structure.",

keywords = "Antigen, Constant domain, Immunoglobulin, Isotype, SAXS, Variable domain, X-ray crystallography",

author = "Ertan Eryilmaz and Alena Janda and Jungwook Kim and Cordero, {Radames J.B.} and David Cowburn and Arturo Casadevall",

note = "Funding Information: Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences , under Contract No. DE-AC02-98CH10886. Molecular graphics and analyses were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from the National Institutes of Health ( National Center for Research Resources grant 2P41RR001081 , National Institute of General Medical Sciences grant 9P41GM103311 ). AC is supported by NIH awards AI033774 , HL059842 , and AI033142 . RJBC was supported in part by the Training Program in Cellular and Molecular Biology and Genetics , T32 GM007491 . The Casadevall laboratory is part and participates in the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center funded by the National Institutes of Health (NIH AI-51519 ).",

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doi = "10.1016/j.molimm.2013.06.006",

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AU - Eryilmaz, Ertan

AU - Janda, Alena

AU - Kim, Jungwook

AU - Cordero, Radames J.B.

AU - Cowburn, David

AU - Casadevall, Arturo

N1 - Funding Information: Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences , under Contract No. DE-AC02-98CH10886. Molecular graphics and analyses were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from the National Institutes of Health ( National Center for Research Resources grant 2P41RR001081 , National Institute of General Medical Sciences grant 9P41GM103311 ). AC is supported by NIH awards AI033774 , HL059842 , and AI033142 . RJBC was supported in part by the Training Program in Cellular and Molecular Biology and Genetics , T32 GM007491 . The Casadevall laboratory is part and participates in the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center funded by the National Institutes of Health (NIH AI-51519 ).

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N2 - Until relatively recently the immunoglobulin molecule was viewed as composed of two independent domains comprised of the variable (V) and constant (C) regions. However, recent work has established that the C region mediates allosteric changes in the V region that can influence specificity and affinity. To further explore cross-domain interrelationship in murine IgG structure we carried out solution small angle X-ray scattering (SAXS) measurements for four V region identical IgG isotypes. SAXS analysis revealed elongated Y-shaped structures in solution with significantly different, isotype-dependent domain orientations. To further explore local C region effects on the V region, the IgG3 Fab crystal structure from the same family was determined to 2.45Å resolution. The IgG3 Fab crystal structure differs from a closely related previously solved IgG1 Fab revealing significant structural differences, which may account for isotype-related specificity differences in V region identical Abs. Among the four murine isotypes, IgG3 was the most different in solution with regards to overall structure as well as aggregate formation in solution suggesting that the greater apparent affinity of this isotype resulted from polyvalent complexes with enhanced avidity. Our results provide additional evidence that Ig V and C domains influence each other structurally and suggest that V region structure can have significant effects on overall Ig structure.

AB - Until relatively recently the immunoglobulin molecule was viewed as composed of two independent domains comprised of the variable (V) and constant (C) regions. However, recent work has established that the C region mediates allosteric changes in the V region that can influence specificity and affinity. To further explore cross-domain interrelationship in murine IgG structure we carried out solution small angle X-ray scattering (SAXS) measurements for four V region identical IgG isotypes. SAXS analysis revealed elongated Y-shaped structures in solution with significantly different, isotype-dependent domain orientations. To further explore local C region effects on the V region, the IgG3 Fab crystal structure from the same family was determined to 2.45Å resolution. The IgG3 Fab crystal structure differs from a closely related previously solved IgG1 Fab revealing significant structural differences, which may account for isotype-related specificity differences in V region identical Abs. Among the four murine isotypes, IgG3 was the most different in solution with regards to overall structure as well as aggregate formation in solution suggesting that the greater apparent affinity of this isotype resulted from polyvalent complexes with enhanced avidity. Our results provide additional evidence that Ig V and C domains influence each other structurally and suggest that V region structure can have significant effects on overall Ig structure.

KW - Antigen

KW - Constant domain

KW - Immunoglobulin

KW - Isotype

KW - SAXS

KW - Variable domain

KW - X-ray crystallography

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Global structures of IgG isotypes expressing identical variable regions

Abstract

Keywords

ASJC Scopus subject areas

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