Molecular basis of Coxsackievirus A10 entry using the two-in-one attachment and uncoating receptor KRM1

Area of Science:

• Structural biology
• Virology
• Molecular mechanisms of viral entry

Background:

• Coxsackievirus A10 (CV-A10) causes hand-foot-and-mouth disease (HFMD), a significant global infant health concern.
• The precise mechanisms of CV-A10 viral entry into host cells remain incompletely understood.
• KREMEN1 (KRM1) has been identified as a functional receptor for CV-A10.

Purpose of the Study:

• To elucidate the atomic structures of CV-A10 viral particles and their complex with KRM1.
• To understand the molecular interactions governing CV-A10 binding to KRM1.
• To investigate the role of KRM1 in CV-A10 entry and uncoating under different pH conditions.

Main Methods:

• Determination of atomic structures of CV-A10 viral particles and KRM1 complexes using X-ray crystallography or cryo-electron microscopy.
• Biochemical assays to confirm receptor binding and virion uncoating.
• Analysis of key residues involved in KRM1-CV-A10 interactions.

Main Results:

• Atomic structures reveal KRM1 binds to the CV-A10 VP1 subunit above the canyon, spanning adjacent asymmetric units.
• Key KRM1-binding residues are conserved across KRM1-dependent enteroviruses, suggesting a common entry mechanism.
• KRM1 binding triggers pocket factor release, an event accelerated by acidic pH, facilitating CV-A10 virion uncoating in vitro.

Conclusions:

• KREMEN1 acts as a crucial receptor for CV-A10 entry, mediating viral particle binding and subsequent uncoating.
• The findings provide high-resolution structural insights into the CV-A10 entry pathway.
• KRM1 functions as a dual-action receptor, facilitating both initial attachment and the initiation of viral uncoating.