Molecule of the Month: Arc

Our brain is made up of billions of neurons, which largely communicate with one another through connections called synapses. Learning and memory requires these connections to be dynamically altered based on brain activity, resulting in some synapses becoming strengthened and others weakened. This process is known as synaptic plasticity. Neurons can respond very quickly to stimulation, and some genes, known as "immediate early genes" are turned on within minutes after a signal is received.

Arc (Activity-regulated cytoskeleton-associated protein) is encoded by one of these immediate early genes. Numerous studies have demonstrated that Arc plays a key role in regulating synaptic plasticity and formation of long-term memories in mammals.

Interestingly, scientists have found that Arc protein shares intriguing similarity to some retroviral proteins. Looking closely at the amino acid sequence of Arc, they found that Arc includes a segment similar to the major structural protein of HIV, known as Gag. Specifically, Arc includes a CA domain, which in HIV Gag is responsible for building the capsid shell. Cellular studies have shown that Arc can form RNA-containing capsids that are released from neurons inside extracellular vesicles. Researchers hypothesize that these Arc-containing extracellular vesicles fuse with nearby cells and act as a way for neurons to communicate with one another and regulate synaptic plasticity.

Recent studies focusing on fruit fly homologs of Arc (dArc1 and dArc2) have shown that Arc can form virus-like capsids. dArc1 and dArc2 form small icosahedral capsids made up of 30 hexamers and 12 pentamers (see the capsid formed by dArc1, 6TAP, on the right). The positively-charged C-terminus of dArc1, which could not be seen in the structure, is expected to lie within the capsid and help capture the RNA cargo of the capsid.

How did a brain gene end up behaving like a virus? Research has shown that there is an evolutionary connection between Arc, retroviruses, and virus-like genetic elements called retrotransposons. Retrotransposons are sometimes called “jumping genes” because they can copy and paste themselves into different parts of the genome. One type, known as LTR (long terminal repeat) retrotransposons, shares many features with retroviruses like HIV. For example, they often include a gag gene that encodes capsid proteins. Recent research has shown that LTR transposons, such as the retrotransposon Ty3, can also form icosahedral capsids made up of hexamers and pentamers (see structure comparison on the right). However, unlike retroviruses and Arc, retrotransposons cannot leave their host cells and be transferred to new cells.

Scientists believe that, at some point in the early evolutionary history of mammals, a virus-like retrotransposon was co-opted, or domesticated, to serve a new purpose — in this case, in order to regulate a complex process in the brain. There are a number of other examples where domesticated retroviruses and retrotransposons have been found to play important roles in animal development, including syncytin, a gene with retroviral origins needed for normal placental development, and the retrotransposons HeT-A and TART, which are necessary for maintaining chromosome structure in fruit flies.