Cargo-Adaptor Cooperation Programs Retromer Coat Architecture

Area of Science:

• Cell Biology
• Virology
• Structural Biology

Background:

• Retromer complexes, with sorting nexin (SNX) adaptors, mediate endosomal cargo retrieval.
• The precise mechanisms by which adaptor-cargo interactions dictate retromer coat structure are not fully understood.

Purpose of the Study:

• To identify the specific retromer adaptor involved in human papillomavirus 16 (HPV16) infection.
• To elucidate how adaptor-cargo binding influences retromer coat assembly and membrane tubulation.

Main Methods:

• Identification of sorting nexin 12 (SNX12) as the key retromer adaptor for HPV16.
• Structural analysis using X-ray crystallography to determine cargo recognition modes.
• Cryo-electron tomography to visualize reconstituted retromer assemblies and their lattice configurations.

Main Results:

• SNX12 is essential for HPV16 infection, with the viral L2 capsid protein tail directly interacting with SNX12-retromer complexes.
• Crystal structure reveals a conserved mechanism for cargo recognition by the adaptor.
• Cryo-electron tomography shows retromer arches forming distinct lattice structures (multi-start helices) stabilized by membrane-proximal interfaces, accommodating membrane curvature via hinge-like motions.

Conclusions:

• Cargo and adaptor identity are critical determinants of retromer coat architecture.
• Retromer functions as a programmable system capable of generating specific transport carriers for distinct cellular routes.
• These findings provide insights into viral hijacking of cellular machinery and the fundamental principles of vesicular transport.