Abstract
Mycoplasma genitalium is a human pathogen adhering to host target epithelial cells and causing urethritis, cervicitis and pelvic inflammatory disease. Essential for infectivity is a transmembrane adhesion complex called Nap comprising proteins P110 and P140. Here we report the crystal structure of P140 both alone and in complex with the N-terminal domain of P110. By cryo-electron microscopy (cryo-EM) and tomography (cryo-ET) we find closed and open Nap conformations, determined at 9.8 and 15 Å, respectively. Both crystal structures and the cryo-EM structure are found in a closed conformation, where the sialic acid binding site in P110 is occluded. By contrast, the cryo-ET structure shows an open conformation, where the binding site is accessible. Structural information, in combination with functional studies, suggests a mechanism for attachment and release of M. genitalium to and from the host cell receptor, in which Nap conformations alternate to sustain motility and guarantee infectivity.
Highlights
Mycoplasma genitalium is a human pathogen adhering to host target epithelial cells and causing urethritis, cervicitis and pelvic inflammatory disease
The structure of P140, for which there are no molecular models or experimental phases available, was determined by density modification techniques, starting with a mask derived from the sub-tomogram-averaged map of the whole Nap obtained by cryo-electron tomography
With four heterodimers in the asymmetric unit, the P140–P110N crystals were refined at 2.65 Å resolution to a final model with agreement R and Rfree factors of 18.7 and 22.4, respectively (Supplementary Table 1)
Summary
Mycoplasma genitalium is a human pathogen adhering to host target epithelial cells and causing urethritis, cervicitis and pelvic inflammatory disease. By cryo-electron microscopy (cryo-EM) and tomography (cryo-ET) we find closed and open Nap conformations, determined at 9.8 and 15 Å, respectively. Both crystal structures and the cryo-EM structure are found in a closed conformation, where the sialic acid binding site in P110 is occluded. Structural information, in combination with functional studies, suggests a mechanism for attachment and release of M. genitalium to and from the host cell receptor, in which Nap conformations alternate to sustain motility and guarantee infectivity. This complex is formed by two heterodimers, each consisting of proteins P110 and P1401–6 In addition to their roles in cytadherence and motility, P110 and P140 are immunodominant proteins and constitute the main target of host antibodies during infection[7,8,9]. The C-terminal domains are closely related, with 74 equivalent residues (∼71%) and an RMSD of 2.2 Å
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