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Abstract: In owl monkeys, the typical retroviral restriction factor of primates, TRIM5α, is replaced by TRIMCyp. TRIMCyp consists of the TRIM5 RING, B-box 2 and coiled-coil domains, as well as the intervening linker regions, fused with cyclophilin A. TRIMCyp restricts infection of retroviruses, such as human immunodeficiency virus (HIV-1) and feline immunodeficiency virus (FIV), with capsids that can bind cyclophilin A. The TRIM5 coiled coil promotes the trimerization of TRIMCyp. Here we show that cyclophilin A that is oligomeric as a result of fusion with a heterologous multimer exhibits substantial antiretroviral activity. The addition of the TRIM5 RING, B-box 2 and Linker 2 to oligomeric cyclophilin A generated a protein with antiretroviral activity approaching that of wild-type TRIMCyp. Multimerization increased the binding of cyclophilin A to the HIV-1 capsid, promoting accelerated uncoating of the capsid and restriction of infection. [Copyright &y& Elsevier]

Abstract: The coiled-coil domain of the tripartite motif (TRIM) family protein TRIM5α is required for trimerization and function as an antiretroviral restriction factor. Unlike the coiled-coil regions of other related TRIM proteins, the coiled coil of TRIM5α is not sufficient for multimerization. The linker region between the coiled-coil and B30.2 domains is necessary for efficient TRIM5α trimerization. Most of the hydrophilic residues predicted to be located on the surface-exposed face of the coiled coil can be altered without compromising TRIM5α antiviral activity against human immunodeficiency virus (HIV-1). However, changes that disrupt TRIM5α trimerization proportionately affect the ability of TRIM5α to bind HIV-1 capsid complexes. Therefore, TRIM5α trimerization makes a major contribution to its avidity for the retroviral capsid, and to the ability to restrict virus infection. [Copyright &y& Elsevier]

The activity-regulated cytoskeleton-associated protein, Arc, is highly expressed in neuronal dendrites and is involved in synaptic scaling and plasticity. Arc exhibits homology to the capsid-forming Gag proteins from retroviruses and can encapsulate its own mRNA and transport it to neighboring neurons. However, the molecular events that lead to the assembly of Arc capsids and how the capsid formation is regulated are not known. Here we show that the capsid domain of Arc may transiently form homogeneous oligomers of similar size as capsids formed by full-length Arc. We determined a high-resolution structure of the monomeric Arc capsid domain and mapped the initial structural change in the oligomerization process to the N-terminal part of the capsid domain. Peptide ligands from the NMDA receptor subunits inhibit oligomerization, which suggests that Arc's ability to transfer mRNA between cells may be regulated by protein-protein interactions at the synapse. • The Arc capsid domain has a rigid bilobar structure • The N-terminal subdomain exists in an alternative conformation • Arc CA binds both the GluN2A and GluN2B NMDA receptor subunits • Ligand binding inhibits temperature-induced oligomerization of the Arc CA domain Arc is a domesticated viral protein expressed in neurons and regulates processes underlying cognition and memory consolidation. Here, Nielsen et al. characterize the structure and dynamics of the capsid homology domain of Arc, and demonstrate that Arc interacts directly with several neuroreceptors and that these interactions interfere with domain oligomerization. [ABSTRACT FROM AUTHOR]