Structural Variations in Species B Adenovirus Fibers Impact CD46 Association

Pache, Lars; Venkataraman, Sangita; Reddy, Vijay; Nemerow, Glen R.

doi:10.1128/jvi.00754-08

Cited by 31 publications

(37 citation statements)

References 40 publications

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“…To determine if the observed structural variations overlap cellular receptor binding sites, we mapped the known HAdV-cellular receptor interactions for CAR, CD46, and GD1a glycan on the homology model (16,20,32,44,(48)(49)(50)(51)(52)(53)(54). The two structural variations viewed in a surface filled model (Fig.…”

Section: Resultsmentioning

confidence: 99%

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Ismail

Lee

Dyer

et al. 2016

J Virol

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Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and by in vitro studies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis. IMPORTANCEViruses adapt various survival strategies to gain entry into target host cells. Human adenovirus (HAdV) types are associated with distinct disease conditions, yet evidence for connections between genotype and cellular tropism is generally lacking. Here, we provide a structural and evolutionary basis for the association between specific genotypes within HAdV species D and epidemic keratoconjunctivitis, a severe ocular surface infection. We find that HAdV-D fiber genes of major EKC pathogens, specifically the fiber knob gene region, share a distinct phylogenetic clade. Deeper analysis of the fiber gene revealed that evolutionary pressure at crucial amino acid sites has a significant impact on its structural conformation, which is likely important in host cell binding and entry. Specific amino acids in hot spot residues provide a link to ocular cell tropism and possibly to corneal pathogenesis. Human adenoviruses (HAdVs) are major causes of respiratory disease, gastroenteritis, and keratoconjunctivitis (1-4). HAdV infections are also a major concern in immunocompromised hosts, with fatality rates as high as 55% (5). There are 72 HAdVs currently genotyped in GenBank, which are classified into seven species (HAdV-A to -G) as determined by whole-genome analysis. The majority (n ϭ 47) belong to HAdV-D, including types 8, 37, 53, 54, 56, and 64 (6-12). Each of these has been associated with epidemic keratoconjunctivitis (EKC), a highly contagious ocular surface infection (13). HAdV-D evolves by homologous recombination within genes encoding the major HAdV capsid proteins (14). For example, type 64 (previously typed as 19a) is a recombinant with types 19, 22, and 37 in the hexon, penton ba...

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Section: Resultsmentioning

confidence: 99%

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Ismail

Lee

Dyer

et al. 2016

J Virol

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“…It has been clearly established that Ad11, as well as Ad35, causes infections by engaging CD46 with high affinity (36,37,51). Moreover, transfection with human CD46 cDNA rendered Chinese hamster ovary cells more permissive to infection by all species B Ads, with the exception of Ad3 and Ad7 (25,50), indicating that most species B Ads use CD46 as a receptor.…”

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“…It has been clearly established that Ad11, as well as Ad35, causes infections by engaging CD46 with high affinity (36,37,51). Moreover, transfection with human CD46 cDNA rendered…”

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An Arginine Switch in the Species B Adenovirus Knob Determines High-Affinity Engagement of Cellular Receptor CD46

Persson

Müller

Reiter

et al. 2009

J Virol

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Adenoviruses (Ads) are icosahedral, nonenveloped viruses with a double-stranded DNA genome. The 51 known Ad serotypes exhibit profound variations in cell tropism and disease types. The number of observed Ad infections is steadily increasing, sometimes leading to fatal outcomes even in healthy individuals. Species B Ads can cause kidney infections, hemorrhagic cystitis, and severe respiratory infections, and most of them use the membrane cofactor protein CD46 as a cellular receptor. The crystal structure of the human Ad type 11 (Ad11) knob complexed with CD46 is known; however, the determinants of CD46 binding in related species B Ads remain unclear. We report here a structural and functional analysis of the Ad11 knob, as well as the Ad7 and Ad14 knobs, which are closely related in sequence to the Ad11 knob but have altered CD46-binding properties. The comparison of the structures of the three knobs, which we determined at very high resolution, provides a platform for understanding these differences and allows us to propose a mechanism for productive high-affinity engagement of CD46. At the center of this mechanism is an Ad knob arginine that needs to switch its orientation in order to engage CD46 with high affinity. Quantum chemical calculations showed that the CD46-binding affinity of Ad11 is significantly higher than that of Ad7. Thus, while Ad7 and Ad14 also bind CD46, the affinity and kinetics of these interactions suggest that these Ads are unlikely to use CD46 productively. The proposed mechanism is likely to determine the receptor usage of all CD46-binding Ads.The nonenveloped adenoviruses (Ads) typically cause respiratory infections, with symptoms ranging from the common cold to pneumonia, but they can also infect the eye, urinary tract, and intestine. Individuals with compromised immune systems are especially prone to severe and life-threatening infections caused by Ads (24). The virion measures about 800 Å in diameter and carries a double-stranded DNA genome. Its icosahedral capsid is primarily formed by 240 copies of the hexon and 12 copies of the penton proteins (3). A trimeric, elongated protein called "fiber" protrudes from each of the 12 vertices of the capsid and mediates the initial attachment to target cells by interacting with cell surface receptors. The fiber consists of a globular head, a fibrous shaft, and a tail. The knob mediates interactions with receptors, whereas the tail anchors the fiber to the penton base. The engagement of receptors is followed by viral internalization via clathrin-coated endocytosis (54).A group of highly pathogenic species B Ads use the membrane cofactor protein CD46 as their cellular receptor (18,20,25,44,50). The heavily glycosylated extracellular portion of CD46 is composed of four short consensus repeat (SCR) modules and a 25-amino-acid sequence rich in serine, threonine, and proline residues (the STP region). CD46 inhibits complement activation by binding separately to C3b or C4b and stabilizes them for proteolytic cleavage by factor I, thus preventing conti...

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“…Recent studies have revealed the structure of species B Ad fiber knobs, the mode of interaction with CD46 and several amino acids crucial for CD46 binding in the fiber knob, [28][29][30][31] and that the FG, HI and IJ loops are involved in the association with CD46. [31][32][33] In particular, Phe242 in the FG loop, Arg279 and Ser282 in the HI loop, and Glu302 in the IJ loop are crucial for attachment to CD46 (note that the numbers of amino-acid residues are those of the Ad35 fiber knob).…”

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confidence: 99%

“…An increase in the luciferase production was not observed for the AdF35 vectors with foreign peptides inserted in the IJ loop. The IJ loop of the Ad35 fiber knob is far from the short consensus repeat (SCR)2 in human CD46, compared with Ad serotypes 7 and 11 (Ad11), 28,[30][31][32] suggesting that an RGD peptide inserted into the IJ loop might not be able to make contact with CD46. Unexpectedly, AdF35-FLAG(HI)-L2 also showed increased transduction efficiencies in both cell types.…”

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Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

et al. 2009

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Fiber-substituted adenovirus (Ad) vectors containing fibers of Ad serotype 35 (AdF35) efficiently transduce a variety of human cells because their receptor, human CD46, is ubiquitously expressed on almost all nucleated cells. However, the ubiquitous expression of CD46 might lead to unexpected transduction in untargeted organs. In this study, we developed fiber-modified AdF35 vectors with an integrinbinding Arg-Gly-Asn (RGD) peptide incorporated into the FG, HI or IJ loop, which have been identified as important regions for binding to CD46. Incorporation of foreign peptides into these loops does not inhibit trimerization of the fibers. In CD46-negative cells, fiber-mutant AdF35 vectors containing an RGD peptide in the FG or HI loop showed 6-to 30-fold higher transduction efficiencies in an RGD-peptide-dependent manner than the unmodified AdF35 vectors. In contrast, in CD46-positive cells, insertion of foreign peptides markedly reduced the transduction efficiencies of the AdF35 vectors, indicating that insertion of foreign peptides significantly inhibits binding to CD46. In particular, CD46-mediated transduction was completely diminished by insertion of foreign peptides into the HI loop. Our findings indicate that HI loop is the most suitable domain to mediate a foreign peptide-dependent and CD46-independent transduction by incorporation of foreign peptides into the Ad35 fiber knob.

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Structural Variations in Species B Adenovirus Fibers Impact CD46 Association

Cited by 31 publications

References 40 publications

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

An Arginine Switch in the Species B Adenovirus Knob Determines High-Affinity Engagement of Cellular Receptor CD46

Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

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