Structure of Drosophila melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag

Abstract

The tetrapod neuronal protein ARC and its Drosophila melanogaster homolog, dARC1, have important but differing roles in neuronal development. Both are thought to originate through exaptation of ancient Ty3/Gypsy retrotransposon Gag, with their novel function relying on an original capacity for self-assembly and encapsidation of nucleic acids. Here, we present the crystal structure of dARC1 CA and examine the relationship between dARC1, mammalian ARC, and the CA protein of circulating retroviruses. We show that while the overall architecture is highly related to that of orthoretroviral and spumaretroviral CA, there are substantial deviations in both amino- and carboxyl-terminal domains, potentially affecting recruitment of partner proteins and particle assembly. The degree of sequence and structural divergence suggests that Ty3/Gypsy Gag has been exapted on two separate occasions and that, although mammalian ARC and dARC1 share functional similarity, the structures have undergone different adaptations after appropriation into the tetrapod and insect genomes.

Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc

“…Therefore, the turn seems vital to the formation of the capsid hexa- and pentamers. An interesting discrepancy between the domain-swapped dimer, the capsid structure, and the recently published crystal structure of the dArc1 CT domain [55], is the presence of the N-terminal tail preceding the NL (residues 29-44 in dArc2, residues 41-57 in dArc1). In the capsid structures of both dArc isoforms, the tail packs into the exposed hydrophobic core of the lobe (Fig 3B), and Phe32 and Phe39 are observed in two hydrophobic pockets and Ser40 interacts directly with Lys78 and Ser79, of the α2 kink, via hydrogen bonding.…”

“…Looking at the conservation mapped onto the dArc2-NL structure, no clear cues are observed; rather, conserved residues are evenly dispersed along the folded structure (Fig 5C). In the structures of the dArc1 and dArc2 capsid [20] as well as the crystal structure of a longer dArc1 construct [55], the NL has the canonical fold without domain swapping. These features imply that the domain-swapped dArc2-NL structure might be due to crystallization of one domain alone, but it confirms the general capability of CA domains to dimerize through different modes, including domain swapping [53,54,59,77].…”

Silencing and Transcriptional Regulation of Endogenous Retroviruses: An Overview

“…More recently, the co-option of an ERV Gag protein has been explored. Activity-regulated cytoskeleton-associated (ARC) proteins generate virus-like particles, perform intercellular mRNA transfer in neurons and fulfill important functions in neuronal development [177][178][179]. ARC proteins were derived from a Ty3/Gypsy retrotransposon Gag, and its functions of self-assembly and encapsidation of nucleic acids have been repurposed for the benefit of the host [177].…”

Characterization of the C-terminal tail of the Arc protein

“…Furthermore, Nielsen et al produced the capsid domain of rat Arc (Arc 206-364 ) that includes the N-lobe and the C-lobe, and solved its structure using the solution NMR method [ 20 ]. Recently, Cottee et al and Erlendsson et al studied the structure of Arc in fruit fly ( Drosophila ) using the x-ray crystallography and cryo-electron microscopy methods [ 21 , 22 ]. Different from rat and other mammal species, the fruit fly has two copies of Arc protein: Arc1 and Arc2; Arc1 has 254 amino-acid residues and Arc2 has 193 amino-acid residues.…”

“…Different from rat and other mammal species, the fruit fly has two copies of Arc protein: Arc1 and Arc2; Arc1 has 254 amino-acid residues and Arc2 has 193 amino-acid residues. Both Arc1 and Arc2 have a capsid domain, whose structure closely resembles the structure of the capsid domain of Arc in rat [ 21 , 22 ]. In addition, Arc1 has a C-terminal tail, which is absent in Arc2.…”