Monomer/dimer transition of the caspase-recruitment domain of human Nod1.
Nod1 is an essential cytoplasmic sensor for bacterial peptidoglycans in the innate immune system. The caspase-recruitment domain of Nod1 (Nod1_CARD) is indispensable for recruiting a downstream kinase, receptor-interacting protein 2 (RIP2), that activates nuclear factor-kappaB (NF-kappaB). The crystal structure of human Nod1_CARD at 1.9 A resolution reveals a novel homodimeric conformation. Our structural and biochemical analysis shows that the homodimerization of Nod1_CARD is achieved by swapping the H6 helices at the carboxy termini and stabilized by forming an interchain disulfide bond between the Cys39 residues of the two monomers in solution and in the crystal. In addition, we present experimental evidence for a pH-sensitive conformational change of Nod1_CARD. Our results suggest that the pH-sensitive monomer/dimer transition is a unique molecular property of Nod1_CARD.
Srimathi
Thiagarajan
T
Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Robbins
Sheila L
SL
Dubas
Rachel L
RL
Hasegawa
Mizuho
M
Inohara
Naohiro
N
Park
Young Chul
YC
D002850:Chromatography, Gel; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D053474:Nod1 Signaling Adaptor Protein / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
D004220:Disulfides; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein