EMD-31628
Structure of the Clade 2 C. difficile TcdB in complex with its receptor TFPI
EMD-31628
Single-particle3.2 Å

Map released: 23/02/2022
Last modified: 30/10/2024
Sample Organism:
Clostridioides difficile,
Homo sapiens
Sample: TFPI-TcdB4 complex
Fitted models: 7v1n (Avg. Q-score: 0.441)
Deposition Authors: Luo J, Yang Q
Sample: TFPI-TcdB4 complex
Fitted models: 7v1n (Avg. Q-score: 0.441)
Deposition Authors: Luo J, Yang Q
TFPI is a colonic crypt receptor for TcdB from hypervirulent clade 2 C. difficile.
Luo J,
Yang Q,
Zhang X,
Zhang Y,
Wan L,
Zhan X
,
Zhou Y,
He L
,
Li D,
Jin D,
Zhen Y,
Huang J,
Li Y,
Tao L
(2022) Cell , 185 , 980 - 994.e15



(2022) Cell , 185 , 980 - 994.e15
Abstract:
The emergence of hypervirulent clade 2 Clostridioides difficile is associated with severe symptoms and accounts for >20% of global infections. TcdB is a dominant virulence factor of C. difficile, and clade 2 strains exclusively express two TcdB variants (TcdB2 and TcdB4) that use unknown receptors distinct from the classic TcdB. Here, we performed CRISPR/Cas9 screens for TcdB4 and identified tissue factor pathway inhibitor (TFPI) as its receptor. Using cryo-EM, we determined a complex structure of the full-length TcdB4 with TFPI, defining a common receptor-binding region for TcdB. Residue variations within this region divide major TcdB variants into 2 classes: one recognizes Frizzled (FZD), and the other recognizes TFPI. TFPI is highly expressed in the intestinal glands, and recombinant TFPI protects the colonic epithelium from TcdB2/4. These findings establish TFPI as a colonic crypt receptor for TcdB from clade 2 C. difficile and reveal new mechanisms for CDI pathogenesis.
The emergence of hypervirulent clade 2 Clostridioides difficile is associated with severe symptoms and accounts for >20% of global infections. TcdB is a dominant virulence factor of C. difficile, and clade 2 strains exclusively express two TcdB variants (TcdB2 and TcdB4) that use unknown receptors distinct from the classic TcdB. Here, we performed CRISPR/Cas9 screens for TcdB4 and identified tissue factor pathway inhibitor (TFPI) as its receptor. Using cryo-EM, we determined a complex structure of the full-length TcdB4 with TFPI, defining a common receptor-binding region for TcdB. Residue variations within this region divide major TcdB variants into 2 classes: one recognizes Frizzled (FZD), and the other recognizes TFPI. TFPI is highly expressed in the intestinal glands, and recombinant TFPI protects the colonic epithelium from TcdB2/4. These findings establish TFPI as a colonic crypt receptor for TcdB from clade 2 C. difficile and reveal new mechanisms for CDI pathogenesis.