Structural and functional insights into sorting nexin 5/6 interaction with bacterial effector IncE.

Area of Science:

• Cell Biology
• Structural Biology
• Microbiology

Background:

• Endosomal trafficking is crucial for cellular functions and is targeted by pathogens.
• The retromer complex and sorting nexins (SNXs) regulate endosomal transport.
• Chlamydia trachomatis effector IncE targets SNX5/6 but its mechanism is unknown.

Purpose of the Study:

• To elucidate the molecular mechanism by which IncE inhibits retromer-mediated endosomal trafficking.
• To determine the structural basis of the interaction between IncE and SNX5.

Main Methods:

• X-ray crystallography to determine the structure of SNX5 PX domain bound to IncE.
• Analysis of the SNX5/6-IncE interaction interface.
• Functional assays to assess the role of the interaction in IncE localization and function.

Main Results:

• The crystal structure reveals IncE binds to a conserved hydrophobic groove on SNX5 via its unique helical hairpin.
• This interaction is specific to SNX5/6 and is essential for IncE's cellular localization and inhibitory activity.
• IncE blocks the recruitment of CI-MPR cargo to retromer-associated endosomes.

Conclusions:

• IncE specifically targets SNX5/6 through a unique structural interaction.
• This interaction disrupts retromer function, inhibiting endosomal trafficking.
• The study highlights pathogen strategies to hijack host cellular machinery.