The structure of enteric adenovirus 41 published in Science Advances

The publication lag phase of our group has officially ended as our first paper just appeared online in Science Advances! In a really exciting collaboration with our Umeå colleagues Annasara Lenman and Niklas Arnberg, our postdoc Karim Rafie determined the first structure of an enteric adenovirus: HAdV-F41, or “ad41” to adenovirus aficionados.

The enteric adenoviruses (40 & 41) are odd members of the human adenoviruses since they cause gastrointestinal disease. Until quite recently they were thought to be “niche” pathogens but advances in diagnostic methods have show that they are one of the most prominent causes of diarrhoea in young children. Diarrhoea may not be thought of as a deadly disease in the Western world, but it frequently is in developing countries. Adenovirus-induced diarrhoea is estimates to kill ~100,000 people/year worldwide, with half of them being children below five years of age.

We are happy that Science Advances is an open access journal since that means you can all read the paper yourselves! But to provide some encouragement to do so, here is a very subjective description of some highlights:

Figure 1 gives you a primer on adenovirus structure. A dizzying number of proteins build up this large capsid – the model of the asymmetric unit has 34 polypeptide chains! As an admission of our imperfection, we didn’t manage to resolve the fibres which are key attachment factors. Enteric AdVs are unique in having two different kinds of fibres.

So how does this enteric adenovirus manage to make it through the gut intact? In Figure 2 we try to answer that. Karim acidified the virus and determined its structure at pH=4. No major change in structure, this thing is acid-proof! We also saw that the enteric adenovirus exposes less charged (i.e. pH-dependent) residues on its outer surface as compared to adenoviruses that cause respiratory and ocular infections.

Figure 3 shows one of the most distinct and intriguing features of the enteric adenovirus. In other human adenoviruses, several copies of protein IX snake their way across the entire outside of the capsid and hold on to each other, like a family of Midgard snakes. In the enteric adenovirus, the IX snakes are instead rearing their heads all over the virus capsid – the “head” being the C-terminal half of IX which is projecting out in a flexible manner. What does it do there? We’d love to know.

At this point we couldn’t contain our curiosity over how this virus capsid is assembled. In figure 4 we focus on the so-called penton base protein. This protein plays a crucial role in virus assembly since it sits at the vertices (i.e. “pointy parts”) of the capsid and connects the fibres to it. We show that the penton base protein changes its structure in many subtle ways when it transitions from a free homopentamer to being a part of the capsid.

Lastly, figure 5 offers a real nugget both for adenovirologists and fans of structural biology. When Karim had built all the large proteins into the ad41 model, he noticed one shorter but well-resolved peptide chain on the inside of the virus capsid. This chain seemed to contain enough information (for instance two distinct, bulky sidechains) that it was worth trying to find out what it was. In a Sherlock Holmesian mission which is described in the supplement, Karim combined different sources of information to arrive at one candidate being more likely than any other. To our excitement, this candidate was protein V, which is described in the literature to bridge the capsid and the DNA genome. Our excitement was further increased when we found a very similar-looking chain in the two previously published human adenovirus structures (5 & 26), where it had not been assigned an identity. We think there is room for more work on the identity and function of this chain , but the hypothesis that it is the anchoring point for the genome makes a lot of sense to us.

Complete reference:

Karim Rafie*, Annasara Lenman*, Johannes Fuchs, Anandi Rajan, Niklas Arnberg†, Lars-Anders Carlson†. The structure of enteric human adenovirus 41—A leading cause of diarrhea in children. Science Advances, published online 8 January 2021

DOI: 10.1126/sciadv.abe0974