TLR folding by chaperones GP96 and CNPY3

Stable Identifier
Reaction [binding]
Homo sapiens
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GP96 (also known as GRP94, HSP90b1), a paralogue of HSP90 in the endoplasmic reticulum, acts as a chaperone for some integrines and Toll-like receptors. Macrophages or B-cells from gp96 knockout mice have abrogated function of TLR2, 4, 5, 7 and 9, but not TLR3 (Yang Y et al 2007, Liu B and Li Z 2008, Staron M et al 2010). GP96 interacts with TLRs and integrines via its C-terminal hydrophobic domain, formed by residues 652-678 (Wu S et al 2012). GP96 functions as a V-shaped dimer in ATP-dependent manner, however it remains unclear how ATP hydrolysis-dependent conformational changes of GP96 are regulated (Li Z and Srivastava PK 1993).

GP96 forms a complex with co-chaperone CNPY3, also known as PRAT4A. GP96-CNPY3 promotes the proper post-translational ectodomain folding of TLRs, but not TLR3 (Liu B et al 2010).

Literature References
PubMed ID Title Journal Year
18509083 Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin

Liu, B, Li, Z

Blood 2008
17275357 Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages

Dai, J, Liu, B, Lefrançois, L, Srivastava, PK, Yang, Y, Zammit, DJ, Li, Z

Immunity 2007
22223641 The Molecular Chaperone gp96/GRP94 Interacts With Toll-Like Receptors And Integrins Via Its C-Terminal Hydrophobic Domain

Guo, B, Liu, B, Gewirth, D, Wu, S, Hong, F, Li, Z

J Biol Chem 2012
20865800 Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone

Bona, R, Staron, M, Liu, B, Han, D, Li, Y, Qiu, Z, Yang, Y, Hao, B, Wu, S, Hong, F, Li, Z, Li, Y

Nat Commun 2010
8344253 Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation

Srivastava, PK, Li, Z

EMBO J 1993
19965672 gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis

Aguila, HL, Li, J, Liu, B, Staron, M, Yang, Y, Shen, Y, Zúñiga-Pflücker, JC, Li, Z, Goldschneider, I

Blood 2010
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