||The Chlamydia trachomatis immunodominant antigen Pgp3 is a trimer ∼150 Å in length with globular assemblies connected by a coiled coil with an unusual right-handed superhelical twist. The single tryptophan (yellow) in each 269-residue chain is prominently displayed in the trimeric C-terminal assembly, which is reminiscent of the trimeric tumor necrosis factor family of cytokines. The three polypeptide chains intertwine and swap structural elements in the globular N-terminal assembly, the interior of which is sealed from solvent by a trio of phenylalanine residues (pink).
A protein secreted by Chlamydia trachomatis, the bacterium that causes chlamydia, has an unusual structure, according to scientists in the School of Medicine at The University of Texas Health Science Center San Antonio. The shape of the protein Pgp3 is distinctive — sort of like an Eiffel Tower of proteins.
“From a structural standpoint, the protein is very odd indeed,” said P. John Hart, senior author of the research, which was described in The Journal of Biological Chemistry. “This long and slender molecule contains a fusion of structural motifs that resemble those typically found in viral and not bacterial proteins.”
The Pgp3 protein is a chlamydial virulence factor that is hypothesized to enhance the bug’s ability to infect its human host and then evade host defenses.
“Although my lab has worked on this protein for many years and gained a great deal of knowledge on it, we still don’t know what roles it may play in chlamydial pathogenesis,” said co-lead author Guangming Zhong. “With the structural information uncovered in this paper, we can now test many hypotheses.”
Chlamydia infection induces inflammatory pathology in humans, and Pgp3 may contribute to the pathology by activating inflammation via one of its structural features uncovered in the crystal structure, said Zhong. This is the second chlamydial virulence factor that Zhong’s laboratory has identified; the first was a protein called CPAF.
The Pgp3 structural work was performed by Hart and his group, Zhong said. The group included Ahmad Galaleldeen, who is the other co-lead author of the research and who is now at St. Mary’s University in San Antonio; Alexander Taylor at UT Health Science Center X-ray Crystallography Core Laboratory; Jonathan Schuermann, now at the Advanced Light Source at Argonne National Labs; Stephen Holloway and Ding Chen, both at UT Health Science Center.
“The independently folded C-terminal domains of the trimeric Pgp3 protein resemble the tumor necrosis factor family of cytokines,” Hart said. “The unique N-terminal domain is formed by reciprocal swapping interactions of structural elements coming from each polypeptide chain. The NTD and CTDs are connected by a lengthy triple-helical coiled-coil with an unusual right-handed twist. We used a divide-and-conquer strategy to engineer truncation variants lacking the triple-helical coiled-coil, which permitted high-resolution structure determinations of the Pgp3 NTD and CTDs. The structures of these domains were then positioned into the moderate-resolution electron density map for the ∼150 angstrom-long full-length protein. Once properly placed, the electron density for the full-length Pgp3 protein improved significantly, and the connecting triple-helical coiled-coil came into view.”
According to the U.S. Centers for Disease Control and Prevention, more than 1.4 million new cases of chlamydia were reported in 2011 across the 50 states and the District of Columbia. But the CDC says as many cases go unreported, because most people with chlamydia have no symptoms and do not seek testing. If left untreated, chlamydia can damage a woman’s reproductive system permanently. This can lead to ectopic pregnancy, pelvic inflammatory disease and infertility. The disease burden worldwide is magnitudes greater, with new cases numbering in the dozens of millions per year.
Will Sansom (firstname.lastname@example.org) is executive director of media communications at The University of Texas Health Science Center San Antonio.