The structure of enteric human adenovirus 41 - a leading cause of diarrhea in children

Rafie, Karim; Lenman, Annasara; Fuchs, Johannes; Rajan, A.; Arnberg, Niklas; Carlson, Lars-Anders

doi:10.1101/2020.07.01.181735

Cited by 11 publications

(19 citation statements)

References 67 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Particles were manually picked and subjected to reference-free 2D classification and well-resolved classes were combined and subjected to mask-less three-dimensional (3D) classification, applying icosahedral symmetry [I3 according to Crowther ( 68 )]. A low-pass–filtered (30 Å) volume of HAdV-F41 ( 69 ) was used as a reference volume. Particles were classified into two classes, resulting in 93% of particles allocated to one well-resolved class which was used for downstream processing.…”

Section: Methodsmentioning

confidence: 99%

Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46

Persson

John

Rafie

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector-based vaccines depends on functional interactions with receptors on host cells. Adenoviruses of different species are assumed to enter host cells mainly by interactions between the knob domain of the protruding fiber capsid protein and cellular receptors. Using a cell-based receptor-screening assay, we identified CD46 as a receptor for HAdV-D56. The function of CD46 was validated in infection experiments using cells lacking and overexpressing CD46, and by competition infection experiments using soluble CD46. Remarkably, unlike HAdV-B types that engage CD46 through interactions with the knob domain of the fiber protein, HAdV-D types infect host cells through a direct interaction between CD46 and the hexon protein. Soluble hexon proteins (but not fiber knob) inhibited HAdV-D56 infection, and surface plasmon analyses demonstrated that CD46 binds to HAdV-D hexon (but not fiber knob) proteins. Cryoelectron microscopy analysis of the HAdV-D56 virion–CD46 complex confirmed the interaction and showed that CD46 binds to the central cavity of hexon trimers. Finally, soluble CD46 inhibited infection by 16 out of 17 investigated HAdV-D types, suggesting that CD46 is an important receptor for a large group of adenoviruses. In conclusion, this study identifies a noncanonical entry mechanism used by human adenoviruses, which adds to the knowledge of adenovirus biology and can also be useful for development of adenovirus-based vaccine vectors.

show abstract

Section: Methodsmentioning

confidence: 99%

Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46

Persson

John

Rafie

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…These observations indicate that the triskelion motif is critical for capsid binding, while the triskelion-carrying proteins are hotspots for AdV evolution, linked to capsid stabilization, interaction with host factors (because of their accessible location on the capsid surface) and consequently, tropism. Indeed, even within HAdVs, protein IX variations may be related to tropism determination, as recently shown by the structure of the enteric HAdV-F41 (Pérez-Illana et al, 2020;Rafie et al, 2020).…”

Section: Discussionmentioning

confidence: 81%

“…Alternatively, U1 and U2 may correspond to the genus specific proteins LH2 and p32k. We favour this last possibility, since the other candidates are also present in mastadenoviruses, but no equivalent densities have been detected in the structures solved so far (Dai et al, 2017;Liu et al, 2010;Pérez-Illana et al, 2020;Rafie et al, 2020;Yu et al, 2017). Both LH2 and p32k have positive charge (isoelectric point 11.02 for p32k, 8.59 for LH2) suggesting they interact with the genome, and are predicted to be predominantly α-helical.…”

Section: Discussionmentioning

confidence: 91%

Near Atomic Structure of an Atadenovirus Reveals a Conserved Capsid-Binding Motif and Intergenera Variations in Cementing Proteins

Marabini

Condezo

Gómez-Blanco

et al. 2020

Preprint

View full text Add to dashboard Cite

Little is known about the basic biology of non-human adenoviruses, which could be alternative vectors free of issues posed by preexisting immunity to human adenoviruses. We present the cryo-EM structure of a lizard atadenovirus, LAdV-2, at 3.4 Å resolution. This is the first high resolution structure of an adenovirus with non-mammalian host, and of an adenovirus not belonging to the Mastadenovirus genus. Atadenovirus capsids contain genus specific proteins LH3, p32k, and LH2, and are more thermostable than the more studied human adenoviruses. We find a large conformational difference in the internal vertex protein IIIa between mast- and atadenoviruses, induced by the presence of an extended polypeptide in the region. This polypeptide, as well as α-helical clusters located beneath the icosahedral facet, likely correspond to proteins LH2 and p32k. The external genus specific protein LH3, with a trimeric β-helix fold typical of bacteriophage host attachment proteins, contacts the hexon shell surface via a triskelion structure identical to that used by protein IX in human AdV, revealing a conserved capsid-binding motif and a possible gene duplication event. Altogether, this work shows how the network of minor coat proteins differs between AdV genera and relates to virus evolution and capsid stability properties.

show abstract

“…Similarly, structural studies of the enteric adenovirus Ad-F41 short fiber head revealed a loop in the fiber head that was disordered at neutral pH and ordered at pH 5 (51, 52). Moreover, comparison of the Ad-F41 capsid to that of non-enteric adenoviruses highlighted a surface with relatively few charged residues and an almost unaltered structure at pH 4 (53)…”

Section: Discussionmentioning

confidence: 99%

An unusual aspartic acid cluster in the reovirus attachment fiber σ1 mediates stability at low pH

Glorani

Ruwolt

Holton

et al. 2021

Preprint

View full text Add to dashboard Cite

The reovirus attachment protein σ1 mediates cell attachment and receptor binding and is thought to undergo conformational changes during viral disassembly. σ1 is a trimeric filamentous protein with an α-helical coil-coiled Tail, a triple β-spiral Body, and a globular Head. The Head domain features an unusual and conserved aspartic acid cluster at the trimer interface, which forms the only significant intra-trimer interactions in the Head, and must be protonated to allow trimer formation.Here we show that all domains of σ1 are remarkably thermostable across a wide range of pH, even at the low pH of the stomach. Interestingly, we determine the optimal pH for stability to be between pH 5-6, a value close to the pH of the endosome and of the jejunum. The σ1 Head is stable at acidic and neutral pH, but detrimerizes at basic pH. When Asp345 in the aspartic acid cluster is mutated to asparagine, the σ1 Head loses stability at low pH and is more prone to detrimerize. Overall, the presence of the Body stabilizes the σ1 Head.Our results confirm a role of the aspartic acid cluster as a pH-dependent molecular switch, and highlight its role in enhancing σ1 stability at low pH.

show abstract

The structure of enteric human adenovirus 41 - a leading cause of diarrhea in children

Cited by 11 publications

References 67 publications

Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46

Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46

Near Atomic Structure of an Atadenovirus Reveals a Conserved Capsid-Binding Motif and Intergenera Variations in Cementing Proteins

An unusual aspartic acid cluster in the reovirus attachment fiber σ1 mediates stability at low pH

Contact Info

Product

Resources

About