MRC National Institute for Medical Research, London
Science for Health
The Trim5α binding site involves the whole capsid surface
01 April 2011
Mammalian cells show different susceptibilities to retrovirus infection. Cells from mice exhibit different susceptibility to murine leukaemia virus (MLV) dependent on their genetic backgrounds; cell lines from different primates show defined patterns of lentiviral replication. In many cases, these variations are due to the presence of cellular proteins referred as restriction factors. 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, the recognition process remains poorly defined in the absence of structural information.
To address this question Sada Ohkura, in the laboratory of Jonathan Stoye (pictured) in NIMR’s Division of Virology, developed a procedure for isolating viruses that replicate in the presence of restriction factors. Working with Ian Taylor, in the Division of Molecular Structure, the analysis of these viruses showed that individual mutations across the entire surface of the viral capsid molecule can relieve restriction.
One of the most surprising features of TRIM5α restriction is the ability of TRIM5αs from different species to recognize and restrict multiple unrelated viruses often across different retroviral genera. Escape from TRIM5α of one species does not necessarily lead to escape from another. It seems likely that restriction factor recognition involves extensive weak contacts between factor and virus.
Taken together, these variable determinants of restriction imply that TRIM5α recognizes its targets in a manner significantly different from many protein-protein interactions that involve a small number of highly conserved residues. Rather the interactions are predominantly weak and spread over a large surface. Perhaps these features are implicit in the design of a defence mechanism intended to recognize a wide range of sequence divergent but structurally related retroviral pathogens that contain assembled repeated capsid moieties.
Location of MLV restriction determinants
Click image to view at full-size
Determinants of MLV 2 restriction, side (lower) and top (upper) views of the N-MLV CA-NtD structure are 3 displayed. The protein backbone is shown in cartoon representation together with the 4 semi-transparent molecular surface. Residues involved in restriction factor specificity 5 are shown as sticks.
Original article
Sadayuki Ohkura, David C. Goldstone, Melvyn W. Yap, Kate Holden-Dye, Ian A. Taylor and Jonathan P. Stoye (2011)
Novel Escape Mutants Suggest an Extensive Trim5α Binding Site Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid Protein
PLoS Pathogens 7(3):e1002011. Full text
News categories
© MRC National Institute for Medical Research
The Ridgeway, Mill Hill, London NW7 1AA
Top of page