5c8c
Crystal structure of recombinant coxsackievirus A16 capsid
Structural highlights
FunctionPOLG_CX16T Protein VP1: Forms, together with VP2 and VP3, an icosahedral capsid (pseudo T=3), 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome. Protein VP1 mainly forms the vertices of the capsid. VP1 interacts with host cell receptor to provide virion attachment to target cell. After binding to its receptor, the capsid undergoes conformational changes. VP1 N-terminus (that contains an amphipathic alpha-helix) is externalized, VP4 is released and together, they shape a virion-cell connecting channel and a pore in the host membrane through which RNase-protected transfer of the viral genome takes place. After genome has been released, the channel shrinks (By similarity). Protein VP2: Forms, together with VP1 and VP3, an icosahedral capsid (pseudo T=3), 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome (By similarity). Protein VP3: Forms, together with VP1 and VP2, an icosahedral capsid (pseudo T=3), 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome (By similarity). Protein VP4: Lies on the inner surface of the capsid shell. After binding to the host receptor, the capsid undergoes conformational changes. VP4 is released, VP1 N-terminus is externalized, and together, they shape a virion-cell connecting channel and a pore in the host membrane through which RNase-protected transfer of the viral genome takes place. After genome has been released, the channel shrinks (By similarity). Protein VP0: Protein VP0: VP0 precursor is a component of immature procapsids, which gives rise to VP4 and VP2 after maturation. Allows the capsid to remain inactive before the maturation step (By similarity). Protease 2A: cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut off the capped cellular mRNA transcription (By similarity). Protein 2B: Affects membrane integrity and cause an increase in membrane permeability (By similarity). Protein 2C: Associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity). Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity). Protease 3C: cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind cooperatively to the protease (By similarity). RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity). Publication Abstract from PubMedEnterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the primary causes of the epidemics of hand-foot-and-mouth disease (HFMD) which affect more than a million children in China each year, and lead to hundreds of deaths. Although there has been progress with vaccines for EV71, development of a CVA16 vaccine has proved more challenging, and the EV71 vaccine does not give useful cross-protection, despite the capsid proteins of the two viruses sharing about 80% sequence identity. The structural details of the expanded forms of the capsids, which possess non-native antigenicity are now well understood, but high resolution information for the native antigenic form of CVA16 has been missing. We here remedy this with high resolution X-ray structures of both mature and natural empty CVA16 particles and also of empty recombinant virus-like particles of CVA16 produced in insect cells, a potential vaccine antigen. All three structures are unexpanded native particles and antigenically identical. The recombinant particles have recruited a lipid moiety to stabilise the native antigenic state that is different to that used in a natural virus infection. As expected the mature CVA16 virus is similar to EV71, however structural and immunogenic comparisons highlight differences, which may have implications for vaccine production. IMPORTANCE: Hand-foot-and-mouth disease is a serious public health threat to children in Asian-Pacific countries, resulting in millions of cases. EV71 and CVA16 are the two dominant causative agents of a disease that, whilst usually mild, can cause severe neurological complications, leading to hundreds of deaths. EV71 vaccines do not provide protection against CVA16. A CVA16 vaccine or bivalent EV71/CVA16 vaccine is therefore urgently needed. We report atomic structures for the mature CVA16 virus, natural empty particles, and a recombinant CVA16 virus-like particle that does not contain the viral genome. All three particles have similar structures and identical antigenicity. The recombinant particles produced in insect cells (a system suitable for making vaccine antigen) are stabilised by recruiting from the insect cells a small molecule different to that used by the virus in a normal infection. We present structural and immunogenic comparisons with EV71 to facilitate structure-based drug-design and vaccine development. Structures of coxsackievirus A16 capsids with native antigenicity, implications for particle expansion, receptor binding and immunogenicity.,Ren J, Wang X, Zhu L, Hu Z, Gao Q, Yang P, Li X, Wang J, Shen X, Fry EE, Rao Z, Stuart DI J Virol. 2015 Aug 12. pii: JVI.01102-15. PMID:26269176[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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