6b1t | pdb_00006b1t
Improved cryoEM structure of human adenovirus type 5 with atomic details of minor proteins VI and VII
Structural highlights
Function[CAP6_ADE05] Pre-protein VI: During virus assembly, promotes hexon trimers nuclear import through nuclear pore complexes via an importin alpha/beta-dependent mechanism. By analogy to herpesviruses capsid assembly, might act as a scaffold protein to promote the formation of the icosahedral capsid.[1] [2] [3] [4] [5] Endosome lysis protein: Structural component of the virion that provides increased stability to the particle shell through its interaction with the core-capsid bridging protein. Fibers shedding during virus entry into host cell allows the endosome lysis protein to be exposed as a membrane-lytic peptide. Exhibits pH-independent membrane fragmentation activity and probably mediates viral rapid escape from host endosome via organellar membrane lysis. It is not clear if it then remains partially associated with the capsid and involved in the intracellular microtubule-dependent transport of capsid to the nucleus, or if it is lost during endosomal penetration.[6] [7] [8] [9] [10] Protease cofactor: Cofactor that activates the viral protease. Binds to viral protease in a 1:1 ratio.[11] [12] [13] [14] [15] [CAP3_ADE05] Structural component of the virion that is likely to participate in vertex stabilization and genome packaging. Stabilizes vertices by tethering the penton bases to neighboring peripentonal hexons. Lashes peripentonal hexons to the neighboring hexons thanks to its interaction with hexon-linking protein. As the virus enters the host cell, capsid vertex proteins are shed concomitant with virion acidification in the endosome. During virus assembly, seems to play a role in packaging of viral DNA via its interaction with packaging protein 3.[16] [17] [NP_ADE05] Plays a role in the inhibition of host immune response within the nucleus. Interacts with cellular nucleosomes and immobilizes the host immune danger signal HMGB1 on chromatin. In turn, prevents HMGB1 release out of the cell and thus decreases inflammation. Plays also a role in the wrapping and condensation of the viral DNA. May also promote viral genome import into the nucleus.[HAMAP-Rule:MF_04056] [CAPSP_ADE05] Major capsid protein that self-associates to form penton base pentamers, each in the shape of a pentagon, situated at the 12 vertices of the pseudo T=25 capsid. Involved in virus secondary attachment to host cell after initial attachment by the fiber protein. Binds host integrin heterodimer ITGAV-ITGB5 (alphaV-beta5) thereby triggering clathrin-mediated endocytosis of virions. Mediates initial virus attachment to CXADR-negative cells. Binding to integrins ITGAV-ITGB5 also seems to induce macropinocytosis uptake of the virus. As the virus enters the host cell, penton proteins are shed concomitant with virion acidification in the endosome.[18] [19] [CAPSH_ADE05] Major capsid protein that self-associates to form 240 hexon trimers, each in the shape of a hexagon, building most of the pseudo T=25 capsid. Assembled into trimeric units with the help of the chaperone shutoff protein (By similarity). Transported by pre-protein VI to the nucleus where it associates with other structural proteins to form an empty capsid. Might be involved, through its interaction with host dyneins, in the intracellular microtubule-dependent transport of incoming viral capsid to the nucleus. [CAP8_ADE05] Hexon-linking protein: Structural component of the virion that lashes peripentonal hexons to the hexons situated in the facets thanks to its interaction with the capsid vertex protein. Also binds together hexons of different facets. [CAP9_ADE05] Structural component of the virion that presumably stabilizes the groups of hexons but is dispensable for assembly. During virus entry, recruits the anterograde motor kinesin-1 to the capsid docked at the nuclear pore complex thereby subjecting the docked capsid to a pulling force. The resulting tension leads to capsid disruption, dispersion of capsid fragments toward cell periphery and eventually viral DNA entry into the host nucleus. Publication Abstract from PubMedHuman adenoviruses (Ad) are dsDNA viruses associated with infectious diseases, yet better known as tools for gene delivery and oncolytic anti-cancer therapy. Atomic structures of Ad provide the basis for the development of antivirals and for engineering efforts towards more effective applications. Since 2010, atomic models of human Ad5 have been independently derived from photographic film cryoEM and X-ray crystallography, but discrepancies exist concerning the assignment of cement proteins IIIa, VIII and IX. To clarify these discrepancies, here we have employed the technology of direct electron-counting to obtain a cryoEM structure of human Ad5 at 3.2 A resolution. Our improved structure unambiguously confirmed our previous cryoEM models of proteins IIIa, VIII and IX and explained the likely cause of conflict in the crystallography models. The improved structure also allows the identification of three new components in the cavities of hexons - the cleaved N-terminus of precursor protein VI (pVIn), the cleaved N-terminus of precursor protein VII (pVIIn2), and mature protein VI. The binding of pVIIn2--by extension that of genome-condensing pVII--to hexons is consistent with the previously proposed dsDNA genome-capsid co-assembly for adenoviruses, which resembles that of ssRNA viruses but differs from the well-established mechanism of pumping dsDNA into a preformed protein capsid, as exemplified by tailed bacteriophages and herpesviruses.IMPORTANCE Adenovirus is a double-edged sword to humans - as a widespread pathogen and a bioengineering tool for anti-cancer and gene therapy. Atomic structure of the virus provides the basis for antiviral and application developments, but conflicting atomic models from conventional/film cryoEM and X-ray crystallography for important cement proteins IIIa, VIII, and IX have caused confusion. Using the cutting-edge cryoEM technology with electron counting, we improved the structure of human adenovirus type 5 and confirmed our previous models of cement proteins IIIa, VIII, and IX, thus clarifying the inconsistent structures. The improved structure also reveals atomic details of membrane-lytic protein VI and genome-condensing protein VII and supports the previously proposed genome-capsid co-assembly mechanism for adenoviruses. Atomic Structures of Minor Proteins VI and VII in the Human Adenovirus.,Dai X, Wu L, Sun R, Zhou ZH J Virol. 2017 Oct 4. pii: JVI.00850-17. doi: 10.1128/JVI.00850-17. PMID:28978703[20] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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