Novel Escape Mutants Suggest an Extensive TRIM5α Binding Site
Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid
Protein
After entry into target cells, retroviruses encounter the host restriction
factors such as Fv1 and TRIM5α. While it is clear that these factors target
retrovirus capsid proteins (CA), recognition remains poorly defined in the
absence of structural information. To better understand the binding interaction
between TRIM5α and CA, we selected a panel of novel N-tropic murine
leukaemia virus (N-MLV) escape mutants by a serial passage of replication
competent N-MLV in rhesus macaque TRIM5α (rhTRIM5α)-positive cells using
a small percentage of unrestricted cells to allow multiple rounds of virus
replication. The newly identified mutations, many of which involve changes in
charge, are distributed over the outer ‘top’ surface of N-MLV CA,
including the N-terminal β-hairpin, and map up to 29 Ao apart.
Biological characterisation with a number of restriction factors revealed that
only one of the new mutations affects restriction by human TRIM5α,
indicating significant differences in the binding interaction between N-MLV and
the two TRIM5αs, whereas three of the mutations result in dual sensitivity
to Fv1n and Fv1b. Structural studies of two mutants show
that no major changes in the overall CA conformation are associated with escape
from restriction. We conclude that interactions involving much, if not all, of
the surface of CA are vital for TRIM5α binding.
Vyšlo v časopise:
Novel Escape Mutants Suggest an Extensive TRIM5α Binding Site
Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid
Protein. PLoS Pathog 7(3): e32767. doi:10.1371/journal.ppat.1002011
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002011
Souhrn
After entry into target cells, retroviruses encounter the host restriction
factors such as Fv1 and TRIM5α. While it is clear that these factors target
retrovirus capsid proteins (CA), recognition remains poorly defined in the
absence of structural information. To better understand the binding interaction
between TRIM5α and CA, we selected a panel of novel N-tropic murine
leukaemia virus (N-MLV) escape mutants by a serial passage of replication
competent N-MLV in rhesus macaque TRIM5α (rhTRIM5α)-positive cells using
a small percentage of unrestricted cells to allow multiple rounds of virus
replication. The newly identified mutations, many of which involve changes in
charge, are distributed over the outer ‘top’ surface of N-MLV CA,
including the N-terminal β-hairpin, and map up to 29 Ao apart.
Biological characterisation with a number of restriction factors revealed that
only one of the new mutations affects restriction by human TRIM5α,
indicating significant differences in the binding interaction between N-MLV and
the two TRIM5αs, whereas three of the mutations result in dual sensitivity
to Fv1n and Fv1b. Structural studies of two mutants show
that no major changes in the overall CA conformation are associated with escape
from restriction. We conclude that interactions involving much, if not all, of
the surface of CA are vital for TRIM5α binding.
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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