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Structural and biological properties of human immunoglobulins


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Tableau 3

Residue positions involved in ADCC, CDC, half life and hinge flexibility

ADCC Domain Mutations on IG Effects and references Residues on FCGR Note
IGHG1 CH2 L1.3>V Decreases FcγRI binding(1) Mutation in the LLGG motif (IGHG2-like)
L1.2>V Prevent FcγRI binding(1) T29, A30, V108, G109 on FCGR3B
E1.4 and P30 on FCGR2A		 Mutation in the LLGG motif (IGHG2-like)
Details about contacts with FCGR3B or FCGR2A (see PDB 1iis or 3ry6)
P114>A Reduces ADCC(2) W3 and W26 on FCGR2A and FCGR3B P114 is conserved in all IG
Details about contacts with FCGR3B or FCGR2A (see PDB 1iis or 3ry6)
S85.4>A/E118>A/K119A Strongly increases ADCC (almost 2-fold)(3) E333A and K334A single mutation have been shown to improve binding to only FCGR3A
K109>W Reduces ADCC (more than 2-fold)(3) W26 on FCGR3B and FCGR2A Details about contacts with FCGR3B or FCGR2A (see PDB 1iis or 3ry6)
E1.4>P Prevents FcγRI binding(1) Mutation IGHG2-like
Details about contacts with FCGR3B (see PDB 1iis)
S3>D/A115>L/I117>E Increases ADCC (4) K114 on FCGR3B Details about contacts with FCGR3B (see PDB 1iis)
IGHG2 CH2 VAG->LLGG (1.3/1.2/1.1/1) Restore FcγRI binding (WT doesn't show any binding capacity)(1) Mutation VAG- > LLGG (IGHG1-like)
IGHG2b CH2 E1.2>L Increases FcγRI affinity(5) Mutation LEGG > LLGG (human-like)
IGHG4 CH2 F1.3>L Increases FcγRI affinity(5) Mutation FLGG > LLGG (IGHG1-like)

CDC

CDC Domain Mutations on IG Effects and references
IGHG1 CH2 E118>S Increases C1q binding(6)
K109>W Increases C1q binding(6)
K105>A Reduces C1q binding(2)
D34>A Reduces C1q binding(2)
S3>D/A115>L/I117>E Ablates CDC(4)
IGHG2b CH2 E101>L/K103>A/K105>A IReduces C1q binding(7)
IGHG4 CH2 S116>P Improves CDC(8)

Half life and fab-arm exchange

Half life Domain Mutations on IG Effects and references Residues on FcRn Note
IGHG1 CH2-CH3 M15.1>Y/S16>T/T18>E (CH2)
+ H113>K/N114>F (CH3)		 Increases FcRn binding(9) G47, E48, W49, P50, T52 and D53 Details about contacts with FcRn (see PDB: 1i1a)
IGHG2 CH2 T14>Q Decreases FcRn binding(10)
CH3 M107>L Decreases FcRn binding(10) P50 Details about contacts with FcRn (see PDB: 1i1a)
IGHG3 CH2 R115>H Increases half life(11) E48 and D53 Details about contacts with FcRn (see PDB: 1i1a)

Fab-arm exchange Domain Mutations on IG Effects and references Notes
IGHG4 Hinge S10>P Reduces Fab-arm exchange(12) Mutation PSCP > PPCP (IGHG1-like)
CH3 R88>K Reduces Fab-arm exchange(13) Mutation FFLYSRLT > FFLYSKLT (IGHG1-like)

IMGT references:
  1. [1] Chappel et al. , Proc Natl Acad Sci U S A, 88(20):9036-40 (1991). PMID:1833770
  2. [2] Idusogie et al. , J Immunol., 164(8):4178-84 (2000). PMID:10754313
  3. [3] Shields et al. , J Biol Chem., 276(9):6591-604 (2001). PMID:11096108
  4. [4] Lazar et al. , Proc Natl Acad Sci U S A. , 103(11):4005-10 (2006). PMID:16537476
  5. [5] Duncan et al. , Nature, 332(6164):563-4 (1988). PMID:2965792
  6. [6] Idusogie et al. , J Immunol., 166(4):2571-5 (2001). PMID:11160318
  7. [7] Duncan and Winter, Nature, 332(6166):738-40 (1988). PMID:3258649
  8. [8] Brekke et al. , Immunol Today. , 16(2):85-90 (1995). PMID:7888072
  9. [9] Vaccaro et al. , Nat Biotechnol. , 23(10):1283-8 (2005). PMID:16186811
  10. [10] Hinton et al. , J Biol Chem., 279(8):6213-6 (2004). PMID:14699147
  11. [11] Stapleton et al. , Nat Commun. , 2:599 (2011). PMID:22186895
  12. [12] Labrijn et al. , Nat Biotechnol. , 27(8):767-71 (2009). PMID:19620983
  13. [13] Labrijn et al. , J. Immunol. , 187(6):3238-46 (2011). PMID:21841137
Created:
11/12/2012
Last updated:
22/09/2023
Authors:
Souphatta Sasorith and Marie-Paule Lefranc
Editor:
Chantal Ginestoux