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Cryo-EM maps reveal five-fold channel structures and their modification by gatekeeper mutations in the parvovirus
Suriyasri Subramanian1, Lindsey J Organtini1, Alec Grossman2
1Department of Medicine, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Abstract:
In minute virus of mice (MVM) capsids, icosahedral five-fold channels serve as portals mediating genome packaging, genome release, and the phased extrusion of viral peptides. Previous studies suggest that residues L172 and V40 are essential for channel function. The structures of MVMi wildtype, and mutant L172T and V40A virus-like particles (VLPs) were solved from cryo-EM data. Two constriction points, termed the mid-gate and inner-gate, were observed in the channels of wildtype particles, involving residues L172 and V40 respectively. While the mid-gate of V40A VLPs appeared normal, in L172T adjacent channel walls were altered, and in both mutants there was major disruption of the inner-gate, demonstrating that direct L172:V40 bonding is essential for its structural integrity. In wildtype particles, residues from the N-termini of VP2 map into claw-like densities positioned below the channel opening, which become disordered in the mutants, implicating both L172 and V40 in the organization of VP2 N-termini.
Insights
Minute virus of mice (MVM) channel integrity relies on L172 and V40 residues. Direct bonding between these residues is crucial for MVM capsid structure and VP2 N-termini organization.
Area of Science:
- Structural biology
- Virology
- Biochemistry
Background:
- Minute virus of mice (MVM) capsids utilize five-fold channels for essential processes like genome packaging and release.
- Residues L172 and V40 have been previously implicated as critical for MVM channel function.
Purpose of the Study:
- To elucidate the structural roles of residues L172 and V40 in MVM capsid channel function.
- To investigate the impact of mutations at L172 and V40 on channel integrity and associated structures.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structures of wildtype MVMi and mutant L172T and V40A virus-like particles (VLPs).
- Structural analysis focused on identifying constrictions within the channels and observing alterations in mutant particles.
Main Results:
- Two constriction points, the mid-gate (involving V40) and inner-gate (involving L172 and V40), were identified in wildtype MVM channels.
- Mutation V40A did not disrupt the mid-gate, but both L172T and V40A mutations severely disrupted the inner-gate.
- Direct L172:V40 bonding is essential for the structural integrity of the inner-gate.
- Residues from VP2 N-termini, normally ordered below the channel opening in wildtype, became disordered in the mutants, indicating L172 and V40 involvement in their organization.
Conclusions:
- The direct interaction between L172 and V40 is vital for maintaining the structural integrity of the MVM capsid's inner-gate.
- These residues also play a role in organizing the N-termini of VP2, which are important for channel function and overall capsid structure.
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