Journal: PLoS One / Year: 2013 Title: Three-dimensional structure of the human myeloma IgG2. Authors: Sergey Ryazantsev / Vladimir Tischenko / Christopher Nguyen / Vyacheslav Abramov / Vladimir Zav'yalov / Abstract: Human immunoglobulin G, subclass 2 (hIgG2), plays an important role in immunity to bacterial pathogens and in numerous pathological conditions. However, there is a lack of information regarding the ...Human immunoglobulin G, subclass 2 (hIgG2), plays an important role in immunity to bacterial pathogens and in numerous pathological conditions. However, there is a lack of information regarding the three-dimensional (3D) structure of the hIgG2 molecule. We used electron microscopy (EM), differential scanning microcalorimetry (DSC) and fluorescence for structural analysis of the hIgG2. DSC and fluorescence indicated two types of interaction between CH1 domain of Fab (antigen-binding fragment/subunit) and CH2 domain of Fc (complement fixation fragment/subunit) simultaneously present in the sample: close interaction, which increases the thermostability of both, CH1 and CH2 domains, and weak (or no) interaction, which is typical for most IgGs but not hIgG2. Thermodynamics could not determine if both types of interactions are present within a single molecule. To address this question, EM was used. We employed a single-particle reconstruction and negative staining approach to reveal the three-dimensional structure of the hIgG2. A three-dimensional model of hIgG2 was created at 1.78 nm resolution. The hIgG2 is asymmetrical: one Fab subunit is in close proximity to the upper portion of the Fc subunit (CH2 domain) and the other Fab is distant from Fc. The plane of Fab subunits is nearly perpendicular to Fc. EM structure of the hIgG2 is in good agreement with thermodynamic data: a Fab distant from Fc should exhibit a lower melting temperature while a Fab interacting with Fc should exhibit a higher melting temperature. Both types of Fab subunits exist within one molecule resembling an A/B hIgG2 isoform introduced earlier on physicochemical level by Dillon et al. (2008). In such an arrangement, the access to the upper portion of Fc subunit is partially blocked by a Fab subunit. That might explain for instance why hIgG2 mildly activates complement and binds poorly to Fc receptors. Understanding of the three-dimensional structure of the hIgG2 should lead to better design of antibody-based therapeutics.
History
Deposition
Jun 23, 2011
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Header (metadata) release
Jul 1, 2011
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Map release
Jul 9, 2012
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Update
Mar 26, 2014
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Current status
Mar 26, 2014
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Download / File: emd_1912.map.gz / Format: CCP4 / Size: 2.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation
human IgG2 Mat density map
Voxel size
X=Y=Z: 2.1 Å
Density
Contour Level
By AUTHOR: 0.893 / Movie #1: 0.893
Minimum - Maximum
-0.07153887 - 1.74183214
Average (Standard dev.)
0.08099203 (±0.25468364)
Symmetry
Space group: 1
Details
EMDB XML:
Map geometry
Axis order
X
Y
Z
Origin
-46
-46
-46
Dimensions
92
92
92
Spacing
92
92
92
Cell
A=B=C: 193.2 Å α=β=γ: 90.0 °
CCP4 map header:
mode
Image stored as Reals
Å/pix. X/Y/Z
2.1
2.1
2.1
M x/y/z
92
92
92
origin x/y/z
0.000
0.000
0.000
length x/y/z
193.200
193.200
193.200
α/β/γ
90.000
90.000
90.000
start NX/NY/NZ
-56
-56
-55
NX/NY/NZ
112
112
112
MAP C/R/S
1
2
3
start NC/NR/NS
-46
-46
-46
NC/NR/NS
92
92
92
D min/max/mean
-0.072
1.742
0.081
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Supplemental data
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Sample components
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Entire : Human myeloma immunoglobulin class G, subclass 2, MAT hIgG2 Mat
Entire
Name: Human myeloma immunoglobulin class G, subclass 2, MAT hIgG2 Mat
Components
Sample: Human myeloma immunoglobulin class G, subclass 2, MAT hIgG2 Mat
Protein or peptide: hIgG2 Mat
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Supramolecule #1000: Human myeloma immunoglobulin class G, subclass 2, MAT hIgG2 Mat
Supramolecule
Name: Human myeloma immunoglobulin class G, subclass 2, MAT hIgG2 Mat type: sample / ID: 1000 Details: More than 95 per cent purity. Stored at 4oC for 20 days before usage Oligomeric state: Monomer / Number unique components: 1
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