Crystal Structure of Trichinella spiralis Calreticulin and the Structural Basis of Its Complement Evasion Mechanism Involving C1q

Authors

Zhihui Jia
Wen Yu
Jingmo Li
Mingming Zhang
Bin Zhan
Liming Yan
Zhenhua Ming
Yuli Cheng
Xiaolin Tian
Shuai Shao
Jingjing Huang
Xinping Zhu

Publication Date

1-1-2024

Journal

Frontiers in Immunology

DOI

10.3389/fimmu.2024.1404752

PMID

38690267

PMCID

PMC11059001

PubMedCentral® Posted Date

4-16-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Trichinella spiralis, Complement C1q, Animals, Calreticulin, Immune Evasion, Crystallography, X-Ray, Protein Binding, Molecular Docking Simulation, Helminth Proteins, Complement Activation, Immunoglobulin G, Humans, Antigens, Helminth, Trichinellosis, Complement Pathway, Classical, Protein Conformation, Trichinella spiralis calreticulin, x-ray crystallography structure, immune evasion, C1q, peptide modulator

Abstract

Helminths produce calreticulin (CRT) to immunomodulate the host immune system as a survival strategy. However, the structure of helminth-derived CRT and the structural basis of the immune evasion process remains unclarified. Previous study found that the tissue-dwelling helminth Trichinella spiralis produces calreticulin (TsCRT), which binds C1q to inhibit activation of the complement classical pathway. Here, we used x-ray crystallography to resolve the structure of truncated TsCRT (TsCRTΔ), the first structure of helminth-derived CRT. TsCRTΔ was observed to share the same binding region on C1q with IgG based on the structure and molecular docking, which explains the inhibitory effect of TsCRT on C1q-IgG–initiated classical complement activation. Based on the key residues in TsCRTΔ involved in the binding activity to C1q, a 24 amino acid peptide called PTsCRT was constructed that displayed strong C1q-binding activity and inhibited C1q-IgG–initiated classical complement activation. This study is the first to elucidate the structural basis of the role of TsCRT in immune evasion, providing an approach to develop helminth-derived bifunctional peptides as vaccine target to prevent parasite infections or as a therapeutic agent to treat complement-related autoimmune diseases.