The design of artificial retroviral restriction factors.
In addition to the ability to bind the retroviral capsid protein, the retroviral restriction factors Fv1, Trim5alpha and Trim5-CypA share the common property of containing sequences that promote self-association. Otherwise Fv1 and Trim5alpha appear unrelated. Mutational analyses showed that restriction was invariably lost when changes designed to disrupt the sequences responsible for multimerization were introduced. A novel restriction protein could be obtained by substituting sequences from the self-associating domain of Fv1 for the Trim5 sequences in Trim5-CypA. Similarly, a fusion protein containing cyclophilin A joined to arfaptin2, a protein known to form extended dimers, was also shown to restrict HIV-1. Hence, multimerization of a capsid-binding domain could be the common minimum design feature for capsid-dependent retroviral restriction factors. However, not all domains that promote multimerization can substitute for the N-terminal domains of Fv1 and Trim5alpha. Moreover, only CypA can provide a capsid-binding site with different N-terminal domains. It is suggested that the spatial relationship between the multiple target binding sites may be important for restriction.
Yap
Melvyn W
MW
Division of Virology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Mortuza
Gulnahar B
GB
Taylor
Ian A
IA
Stoye
Jonathan P
JP
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D021984:Cyclophilin A / Q000235:genetics* / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
C101158:ARFIP2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D044966:Anti-Retroviral Agents; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; C103189:Fv1 protein, mouse; D011506:Proteins; D011993:Recombinant Fusion Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D021984:Cyclophilin A