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101.
Brittney L. Gurda Kristin N. Parent Heather Bladek Robert S. Sinkovits Michael A. DiMattia Chelsea Rence Alejandro Castro Robert McKenna Norm Olson Kevin Brown Timothy S. Baker Mavis Agbandje-McKenna 《Journal of virology》2010,84(12):5880-5889
Human bocavirus (HBoV) was recently discovered and classified in the Bocavirus genus (family Parvoviridae, subfamily Parvovirinae) on the basis of genomic similarity to bovine parvovirus and canine minute virus. HBoV has been implicated in respiratory tract infections and gastroenteric disease in children worldwide, yet despite numerous epidemiological reports, there has been limited biochemical and molecular characterization of the virus. Reported here is the three-dimensional structure of recombinant HBoV capsids, assembled from viral protein 2 (VP2), at 7.9-Å resolution as determined by cryo-electron microscopy and image reconstruction. A pseudo-atomic model of HBoV VP2 was derived from sequence alignment analysis and knowledge of the crystal structure of human parvovirus B19 (genus Erythrovirus). Comparison of the HBoV capsid structure to that of parvoviruses from five separate genera demonstrates strong conservation of a β-barrel core domain and an α-helix, from which emanate several loops of various lengths and conformations, yielding a unique surface topology that differs from the three already described for this family. The highly conserved core is consistent with observations for other single-stranded DNA viruses, and variable surface loops have been shown to confer the host-specific tropism and the diverse antigenic properties of this family.Human bocavirus (HBoV), a newly discovered member of the family Parvoviridae, was originally isolated in randomly selected nasopharyngeal aspirates (5). Since this initial discovery, HBoV has also been detected worldwide, predominantly in children under the age of 2 years with respiratory infections, in serum, urine, and fecal samples (40). Symptomatic children commonly exhibit acute diseases of the upper and lower respiratory tracts (7, 36, 44, 56) and, possibly, gastroenteritis (31, 56) though the link to gastroenteritis outbreaks has been questioned (12). It is still unclear if HBoV is the sole etiologic agent of respiratory disease as higher rates of coinfections with other respiratory pathogens such as human rhinovirus and Streptococcus spp. are often observed (4). However, Allander et al. recently reported (4) that HBoV was found in 19% of children with acute wheezing, thereby making it the fourth most common virus, after rhinoviruses, enteroviruses, and respiratory syncytial virus, detected in children exhibiting this symptom. These findings suggest that, at high viral load, HBoV could be an etiologic agent of respiratory tract disease (4). HBoV infection is common in the first few years of life, and clinical research suggests it may follow the primary period for acquisition of human parvovirus B19 (B19) though there is no antigenic cross-reactivity between B19 and HBoV (28, 30). By age 5, most people have circulating antibodies against HBoV, as is also true for other respiratory viruses such as respiratory syncytial virus, rhinoviruses, and human metapneumovirus (17). HBoV has also been identified in adults, with ∼63% of samples tested being seropositive, showing a positive correlation with age and a slight positive bias toward women (14).The Parvoviridae is a family of small, nonenveloped viruses that package a single-stranded DNA (ssDNA) genome of ∼5,000 bases. These viruses are subdivided into two subfamilies: Parvovirinae and Densovirinae (Table (Table1).1). The Parvovirinae are further subdivided into five genera, all of whose members infect vertebrates. The Densovirinae (four genera) infect only invertebrates. Phylogenetic analysis places HBoV in the recently classified Bocavirus genus (Table (Table1).1). In addition to HBoV, numerous parvoviruses circulate among the human population. Among these are the following: several dependoviruses; adeno-associated virus (AAV) serotypes AAV1 to AAV3, AAV5, and AAV9; the Erythrovirus B19; and the newly discovered human parvovirus genotypes 4 (Parv4) and 5 (Parv5) (23, 27, 50). Of these, only B19 had been implicated in disease until the discovery of HBoV and Parv4, which has been isolated from patients who present symptoms of acute HIV infection (50).
Open in a separate windowaAalDNV, Aedes albopictus densovirus; AaeDNV, Aedes aegypti densovirus; BmDNV, Bombyx mori densovirus; BPV, bovine parvovirus; CnMV, canine minute virus; CPV, canine parvovirus; FPV, feline panleukopenia virus; GPV, goose parvovirus; JcDNV, Junonia coenia densovirus; PfDNV, Periplaneta fuliginosa densovirus; SPV, simian parvovirus. *, structure determined by X-ray crystallography; †, structure determined by cryo-EM.bThe number of VPs in the virion capsid.cGroup refers to the surface topologies described in Results and Discussion (HBoV is currently the only bocavirus with a known structure; there is no structure available for Periplaneta fuliginosa densovirus or the brevidensoviruses). NA, structural group not assigned.dThe VP(s) that comprises most of the wild-type virion.The HBoV genome, like that of all members of the Bocavirus genus, contains three open reading frames (ORFs). The first ORF, at the 5′ end, encodes NS1, a nonstructural protein. The next ORF, unique to the bocaviruses, encodes NP1, a second nonstructural protein. The third ORF, at the 3′ end, encodes the two structural capsid viral proteins (VPs), VP1 and VP2. The HBoV VPs share 42% and 43% amino acid sequence identity with the corresponding VPs of bovine parvovirus and canine minute virus, respectively (5). More recently, two additional HBoV-like viruses, HBoV-2 and HBoV-3, were identified in stool samples from children (8, 31). The genome organization of these viruses is identical to that of HBoV, with the NS1, NP1, and VP proteins of HBoV-2 and HBoV-3 being, respectively, ∼80 and 90%, ∼70 and 80%, and ∼80 and 80% identical to the respective proteins in HBoV (8, 31).Parvovirus genomes are packaged into a T=1 icosahedral capsid that is assembled from 60 copies of a combination of up to six types of capsid VPs (VP1 to VP6), all of which share a C terminus. VP1 is always a minor component, typically comprising about five copies per capsid, whereas the smallest VP is always the major component. The unique N-terminal region of VP1 (VP1u) contains a conserved phospholipase A2 (PLA2) motif within the first 131 amino acids that is essential for infection (49, 61). Interestingly, Aleutian mink disease virus (AMDV), the only member of the Amdovirus genus, is the only exception in that this motif is absent, which suggests that this virus employs a different mechanism to escape the endosome during infection (54).The X-ray crystal structures of several parvoviruses show that all VPs contain a conserved, eight-stranded β-barrel motif (βB to βI) that forms the core of the capsid (15). There is also a conserved α-helix (αA) observed in all parvovirus structures determined to date. The bulk of the VP consists of elaborate loops between the strands that form the surface of the capsid. For example, the GH loop between the βG and βH strands is ∼230 residues. The composition and topology of these loops encode several important functions, including tissue tropism, pathogenicity, and the antigenic response directed against each parvovirus during infection (2).A number of parvoviruses have been studied by cryo-electron microscopy (cryo-EM) and three-dimensional (3D) image reconstruction in concert with and complementary to X-ray crystallographic studies (reviewed in reference 15). Reported here is the 3D structure of a recombinant HBoV capsid solved to 7.9-Å resolution using cryo-EM. The capsid of HBoV was compared to that of representative members of the Parvoviridae (Table (Table1)1) with known atomic structures (AAV2, minute virus of mice [MVM], B19, and Galleria mellonella densovirus [GmDNV]) or pseudo-atomic models built into cryo-EM reconstructed density (AMDV) to identify similarities and differences. The capsid topology of the newly emerging HBoV incorporates a combination of surface structural features seen in other members of the Parvovirinae and is closest to that of B19, the only other structurally characterized parvovirus that is pathogenic to humans. A pseudo-atomic model of the HBoV VP2, built into the reconstructed density, identified conserved core secondary structure elements, which are known to be important for parvovirus capsid assembly, and variable surface loops, which likely govern host specific interactions. 相似文献
TABLE 1.
Selected properties of representative members of the ParvoviridaeSubfamily (host) and genus | Member(s)a | No. of VPsb | Groupc | Major VP(s)d |
---|---|---|---|---|
Parvovirinae (vertebrate) | ||||
Parvovirus | MVM*, CPV*, FPV* | 3 | I | VP2 |
Erythrovirus | B19*†, SPV | 2 | III | VP2 |
Dependovirus | AAV2*†, AAV4*†, GPV | 3 | III | VP3 |
Amdovirus | AMDV† | 2 | III | VP2 |
Bocavirus | HBoV†, BPV, CnMV | 2 | NA | VP2 |
Densovirinae (invertebrate) | ||||
Densovirus | GmDNV*, JcDNV† | 4 | II | VP4 |
Iteravirus | BmDNV† | 4-6 | II | VP1-VP4 |
Brevidensovirus | AaeDNV, AalDNV | 2-3 | NA | VP1 or VP2/3 |
Pefudensovirus | PfDNV | 5 | NA | VP1 |
102.
Molecular characterization of the heparin-dependent transduction domain on the capsid of a novel adeno-associated virus isolate, AAV(VR-942) 下载免费PDF全文
Schmidt M Govindasamy L Afione S Kaludov N Agbandje-McKenna M Chiorini JA 《Journal of virology》2008,82(17):8911-8916
A new adeno-associated virus (AAV), referred to as AAV(VR-942), has been isolated as a contaminant of adenovirus strain simian virus 17. The sequence of the rep gene places it in the AAV serotype 2 (AAV2) complementation group, while the capsid is only 88% identical to that of AAV2. High-level AAV(VR-942) transduction activity requires cell surface heparan sulfate proteoglycans, although AAV(VR-942) lacks residues equivalent to the AAV2 R585 and R588 amino acid residues essential for mediating the interaction of AAV2 with the heparan sulfate proteoglycan receptor. Instead, AAV(VR-942) uses a distinct transduction region. This finding shows that distinct domains on different AAV isolates can be responsible for the same activities. 相似文献
103.
Peterson KE Pourciau S Du M Lacasse R Pathmajeyan M Poulsen D Agbandje-McKenna M Wehrly K Chesebro B 《Journal of virology》2008,82(17):8906-8910
Changes in the envelope proteins of retroviruses can alter the ability of these viruses to infect the central nervous system (CNS) and induce neurological disease. In the present study, nine envelope residues were found to influence neurovirulence of the Friend murine polytropic retrovirus Fr98. When projected on a three-dimensional model, these residues were clustered in two spatially separated groups, one in variable region B of the receptor binding site and the other on the opposite side of the envelope. Further studies indicated a role for these residues in virus replication in the CNS, although the residues did not affect viral entry. 相似文献
104.
McLarren KW Severson TM du Souich C Stockton DW Kratz LE Cunningham D Hendson G Morin RD Wu D Paul JE An J Nelson TN Chou A DeBarber AE Merkens LS Michaud JL Waters PJ Yin J McGillivray B Demos M Rouleau GA Grzeschik KH Smith R Tarpey PS Shears D Schwartz CE Gecz J Stratton MR Arbour L Hurlburt J Van Allen MI Herman GE Zhao Y Moore R Kelley RI Jones SJ Steiner RD Raymond FL Marra MA Boerkoel CF 《American journal of human genetics》2010,87(6):905-914
CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development. 相似文献
105.
Genetic diversity of Pierce's disease strains and other pathotypes of Xylella fastidiosa 总被引:1,自引:0,他引:1
Hendson M Purcell AH Chen D Smart C Guilhabert M Kirkpatrick B 《Applied and environmental microbiology》2001,67(2):895-903
Strains of Xylella fastidiosa isolated from grape, almond, maple, and oleander were characterized by enterobacterial repetitive intergenic consensus sequence-, repetitive extragenic palindromic element (REP)-, and random amplified polymorphic DNA (RAPD)-PCR; contour-clamped homogeneous electric field (CHEF) gel electrophoresis; plasmid content; and sequencing of the 16S-23S rRNA spacer region. Combining methods gave greater resolution of strain groupings than any single method. Strains isolated from grape with Pierce's disease (PD) from California, Florida, and Georgia showed greater than previously reported genetic variability, including plasmid contents, but formed a cluster based on analysis of RAPD-PCR products, NotI and SpeI genomic DNA fingerprints, and 16S-23S rRNA spacer region sequence. Two groupings of almond leaf scorch (ALS) strains were distinguished by RAPD-PCR and CHEF gel electrophoresis, but some ALS isolates were clustered within the PD group. RAPD-PCR, CHEF gel electrophoresis, and 16S-23S rRNA sequence analysis produced the same groupings of strains, with RAPD-PCR resolving the greatest genetic differences. Oleander strains, phony peach disease (PP), and oak leaf scorch (OLS) strains were distinct from other strains. DNA profiles constructed by REP-PCR analysis were the same or very similar among all grape strains and most almond strains but different among some almond strains and all other strains tested. Eight of 12 ALS strains and 4 of 14 PD strains of X. fastidiosa isolated in California contained plasmids. All oleander strains carried the same-sized plasmid; all OLS strains carried the same-sized plasmid. A plum leaf scald strain contained three plasmids, two of which were the same sizes as those found in PP strains. These findings support a division of X. fastidiosa at the subspecies or pathovar level. 相似文献
106.
Clemente JC Moose RE Hemrajani R Whitford LR Govindasamy L Reutzel R McKenna R Agbandje-McKenna M Goodenow MM Dunn BM 《Biochemistry》2004,43(38):12141-12151
Protease inhibitor resistance still poses one of the greatest challenges in treating HIV. To better design inhibitors able to target resistant proteases, a deeper understanding is needed of the effects of accumulating mutations and the contributions of active- and nonactive-site mutations to the resistance. We have engineered a series of variants containing the nonactive-site mutations M46I and I54V and the active-site mutation I84V. These mutations were added to a protease clone (V6) isolated from a pediatric patient on ritonavir therapy. This variant possessed the ritonavir-resistance-associated mutations in the active-site (V32I and V82A) and nonactive-site mutations (K20R, L33F, M36I, L63P, A71V, and L90M). The I84V mutation had the greatest effect on decreasing catalytic efficiency, 10-fold when compared to the pretherapy clone LAI. The decrease in catalytic efficiency was partially recovered by the addition of mutations M46I and I54V. The M46I and I54V were just as effective at decreasing inhibitor binding as the I84V mutation when compared to V6 and LAI. The V6(54/84) variant showed over 1000-fold decrease in inhibitor-binding strength to ritonavir, indinavir, and nelfinavir when compared to LAI and V6. Crystal-structure analysis of the V6(54/84) variant bound to ritonavir and indinavir shows structural changes in the 80's loops and active site, which lead to an enlarged binding cavity when compared to pretherapy structures in the Protein Data Bank. Structural changes are also seen in the 10's and 30's loops, which suggest possible changes in the dynamics of flap opening and closing. 相似文献
107.
Govindasamy L Pedersen B Lian W Kukar T Gu Y Jin S Agbandje-McKenna M Wu D McKenna R 《Journal of structural biology》2004,148(2):226-235
The biosynthetic enzyme for the neurotransmitter acetylcholine, choline acetyltransferase (ChAT) (E.C. 2.3.1.6), is essential for the development and neuronal activities of cholinergic systems involved in many fundamental brain functions. ChAT catalyzes the transfer of an acetyl group from acetyl-coenzyme A to choline to form the neurotransmitter acetylcholine. Since its discovery more than 60 years ago much research has been devoted to the kinetic studies of this enzyme. For the first time we report the crystal structure of rat ChAT (rChAT) to 1.55 A resolution. The structure of rChAT is a monomer and consists of two domains with an interfacial active site tunnel. This structure, with the modeled substrate binding, provides critical insights into the molecular basis for the production of acetylcholine and may further our understanding of disease causing mutations. 相似文献
108.
Duda DM Tu C Fisher SZ An H Yoshioka C Govindasamy L Laipis PJ Agbandje-McKenna M Silverman DN McKenna R 《Biochemistry》2005,44(30):10046-10053
The residue phenylalanine 198 (Phe 198) is a prominent cause of the lower activity of human carbonic anhydrase III (HCA III) compared with HCA II and other isozymes which have leucine at this site. We report the crystal structures of HCA III and the site-directed mutant F198L HCA III, both at 2.1 A resolution, and the enhancement of catalytic activity by exogenous proton donors containing imidazole rings. Both enzymes had a hexahistidine extension at the carboxy-terminal end, used to aid in purification, that was ordered in the crystal structures bound in the active site cavity of an adjacent symmetry-related enzyme. This observation allowed us to comment on a number of possible binding sites for imidazole and derivatives as exogenous proton donors/acceptors in catalysis by HCA III. Kinetic and structural evidence indicates that the phenyl side chain of Phe 198 in HCA III, about 5 A from the zinc, is a steric constriction in the active site, may cause altered interactions at the zinc-bound solvent, and is a binding site for the activation of catalysis by histidylhistidine. This suggests that sites of activation of the proton-transfer pathway in carbonic anhydrase are closer to the zinc than considered in previous studies. 相似文献
109.
With human genetic technologies now an important area of European research and development, bioethics is becoming increasingly important in its regulation and future. As regulatory decisions are also statements about who should get what, bioethics cannot avoid political controversy. Can bioethics sustain its claimed role as authoritative adviser to decision makers, or will its attempts to reach a consensus on human genetic technologies be perceived as the actions of an ambitious interest group? What, in short, is its political future in Europe and elsewhere? 相似文献
110.
Plasmid RP4 was used to mobilize the agrocin 84-encoding plasmid, pAg396, from Agrobacterium tumefaciens strain 396 to A. tumefaciens C58 and C58CI as well as Rhizobium meliloti. It was transferred to, but not stably maintained in, R. leguminosarum. It could not be transferred to R. lupini, R. japonicum or R. trifolii. Plasmid pAg396 did not segregate in R. meliloti and produced levels of agrocin comparable to the parental strain A. tumefaciens 396. The potential of agrocin producing R. meliloti in biological control of crown gall is being investigated. 相似文献