Structure of the Chlamydia trachomatis Immunodominant Antigen Pgp3

Ahmad Galaleldeen,Alexander B Taylor,Ding Chen,Jonathan P Schuermann,Stephen P Holloway,Shuping Hou,Siqi Gong,Guangming Zhong,P John Hart

doi:10.1074/jbc.m113.475012

Abstract

Chlamydia trachomatis infection is the most common sexually transmitted bacterial disease. Left untreated, it can lead to ectopic pregnancy, pelvic inflammatory disease, and infertility. Here we present the structure of the secreted C. trachomatis protein Pgp3, an immunodominant antigen and putative virulence factor. The ∼84-kDa Pgp3 homotrimer, encoded on a cryptic plasmid, consists of globular N- and C-terminal assemblies connected by a triple-helical coiled-coil. The C-terminal domains possess folds similar to members of the TNF family of cytokines. The closest Pgp3 C-terminal domain structural homologs include a lectin from Burkholderia cenocepacia, the C1q component of complement, and a portion of the Bacillus anthracis spore surface protein BclA, all of which play roles in bioadhesion. The N-terminal domain consists of a concatenation of structural motifs typically found in trimeric viral proteins. The central parallel triple-helical coiled-coil contains an unusual alternating pattern of apolar and polar residue pairs that generate a rare right-handed superhelical twist. The unique architecture of Pgp3 provides the basis for understanding its role in chlamydial pathogenesis and serves as the platform for its optimization as a potential vaccine antigen candidate.

Highlights

Pgp3 is an immunogenic protein secreted by Chlamydia trachomatis
The C-terminal domains resemble tumor necrosis factor, the helical coiled-coil has an unusual twist, and the N-terminal domain is a fusion of virus-like structural motifs
The closest Pgp3 C-terminal domain structural homologs include a lectin from Burkholderia cenocepacia, the C1q component of complement, and a portion of the Bacillus anthracis spore surface protein BclA, all of which play roles in bioadhesion

Summary

Background

Pgp is an immunogenic protein secreted by Chlamydia trachomatis. Results: The trimeric Pgp structure reveals globular domains connected by a triple helical coiled-coil. Pgp is a ϳ84-kDa homotrimeric protein [16] both associated with the outer membrane [17] and secreted into the inclusion lumen and the host cell cytosol [8] It is one of the most immunodominant antigens in mammals infected by chlamydial organisms [18, 19]. Purified Pgp is known to stimulate macrophages to release inflammatory cytokines [8], and vaccination with Pgp provides partial protection against challenge infection with chlamydial organisms [20] Together these observations suggest that the protein plays a prominent role in chlamydial pathogenesis and as such could be a promising vaccine antigen candidate. The recent development of a chlamydial plasmid transformation system [14], combined with knowledge of the Pgp structure presented here, provides powerful tools to probe the role of the molecule in chlamydial pathogenesis and may assist in vaccine development

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION

A B D’ C’