Germline-encoded amino acid-binding motifs (shortened GRAB motifs, coined by (1)) are regions in antibodies, mostly in the light chain CDRs, that target specific amino acids on the surface of potential epitopes. For example, a common lysine-binding GRAB motif is D51 in CDR2 of many lambda light chains.
Details
- Lysine-binding GRAB motifs:
- In IgLV3-1, Y32 from CDR1 and N66 from CDR3; IgLV3-10, IgLV3-25, IgLV6-57, and IgLV3-21 have similar motifs (four additional lambda V-gene segments had Y/S32, D51, S/T66 predicted by AlphaFold to fold into similar structures; there are no PDB structures of these)
- In IgLV5-37, instead the residues are Y51, D52C, and N32
- 75% of PDB Ab-Ag structures (24 out of 32) involving these six light chain V-genes maintain this interaction, and lysine was found at edge of epitope
- Asp/Glu-binding GRAB motifs:
- IgHV3-21 CDR2 (S52, S52A, S53, S55, Y56) binds D or E
- Four of eight PDB structures with this heavy chain V-gene have this binding mode
- IgHV3-11 also has this motif, but has no representatives in the PDB
- A second lysine-binding GRAB motif:
- IgHV5-51 CDR2/FW2 residues W33, Y52, D54, D56, sometimes R58 bind lysine in 8 of 10 PDB structures
- Hydrophobic-binding GRAB motif:
- IgKV4-1 Y30A, Y32, Y92 (CDR1 and CDR3) forms nonpolar interactions with antigens, primarily recognizing proline (four examples) but also binding histidine, valine, arginine, alanine (one example each); eight out of 22 PDB IgKV4-1 structures
Figures
Ref (1)
1.
Shrock EL, Timms RT, Kula T, Mena EL, West AP, Guo R, et al. Germline-encoded amino acid–binding motifs drive immunodominant public antibody responses. Science. 2023;380(6640). Available from: https://doi.org/10.1126/science.adc9498