Cryo-EM structure of enteric adenovirus HAdV-F41 highlights structural variations among human adenoviruses

Abstract

Enteric adenoviruses, one of the main causes of viral gastroenteritis in the world, must withstand the harsh conditions found in the gut. This requirement suggests that capsid stability must be different from that of other adenoviruses. We report the 4-Å-resolution structure of a human enteric adenovirus, HAdV-F41, and compare it with that of other adenoviruses with respiratory (HAdV-C5) and ocular (HAdV-D26) tropisms. While the overall structures of hexon, penton base, and internal minor coat proteins IIIa and VIII are conserved, we observe partially ordered elements reinforcing the vertex region, which suggests their role in enhancing the physicochemical capsid stability of HAdV-F41. Unexpectedly, we find an organization of the external minor coat protein IX different from all previously characterized human and nonhuman mastadenoviruses. Knowledge of the structure of enteric adenoviruses provides a starting point for the design of vectors suitable for oral delivery or intestinal targeting.

Adenovirus Structure: What Is New?

“…In the HAdV-C5 cryo-EM model, only four of the seven loops at the top of each hexon monomer could be traced [ 28 ]. In contrast, a recent study of the enteric HAdV-F41 solved all the loops except HVR4 [ 30 ]. In human adenoviruses of species C, HVR1 presents a unique, 32 residue-long acidic loop that confers a large negative charge to the outer capsid surface [ 48 ].…”

“…In human adenoviruses of species C, HVR1 presents a unique, 32 residue-long acidic loop that confers a large negative charge to the outer capsid surface [ 48 ]. In HAdV-F41 and HAdV-D26, HVR1 is shorter than in HAdV-C5 and could be fully traced in cryo-EM maps [ 29 , 30 ]. The acidic HVR-1 in HAdV-C5 seems to be involved in electrostatic interactions with neutralizing defensins, and its absence in species D and F may play a role in determining the enteric or ocular tropism of these viruses, although this aspect is not well understood yet [ 30 , 49 ].…”

“…In HAdV-F41 and HAdV-D26, HVR1 is shorter than in HAdV-C5 and could be fully traced in cryo-EM maps [ 29 , 30 ]. The acidic HVR-1 in HAdV-C5 seems to be involved in electrostatic interactions with neutralizing defensins, and its absence in species D and F may play a role in determining the enteric or ocular tropism of these viruses, although this aspect is not well understood yet [ 30 , 49 ]. In lizard adenovirus type 2 (LAdV-2), an Atadenovirus, the loops are shorter and could be modeled without gaps.…”

“…The penton base protein folds into two domains: a single jellyroll and an upper insertion facing the solvent-exposed exterior ( Figure 2 b) [ 44 , 51 ]. This upper domain contains the hypervariable loop, which due to its flexibility, has not been traced in any of the available HAdV structures [ 7 , 27 , 29 , 30 , 51 ]. In most human adenoviruses, the hypervariable loop bears the RGD sequence, an α v integrin-binding motif.…”

“…Nevertheless, it has been recently shown that HAdV-F41 binds laminin-binding integrins [ 53 ]. Since the RGD loop is also involved in neutralization by the enteric defensin HD5, it has been proposed that lack of both this sequence motif and the acidic HVR1 in hexon may play a role in facilitating infection of intestinal cells by HAdV-F40 and HAdV-F41 [ 30 , 49 ]. Another surface-exposed variable loop presents sequence divergence and different conformations in the human adenoviruses [ 7 , 29 , 30 , 51 ].…”