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Assembly Lecture 11 Biology W3310/4310 Virology Spring 2014 Assembly Lecture 11 Biology W3310/4310 Virology Spring 2014 “Anatomy is des.ny.” --SIGMUND FREUD All virions complete a common set of assembly reac3ons * common to all viruses common to many viruses ©Principles of Virology, ASM Press The structure of a virus parcle determines how it is formed ©Principles of Virology, ASM Press Assembly is dependent on host cell machinery • Cellular chaperones • Transport systems • Secretory pathway • Nuclear import and export machinery Concentrang components for assembly: Nothing happens fast in dilute solu1ons • Viral components oSen visible by light microscopy (‘factories’ or ‘inclusions’) • Concentrate proteins on internal membranes (poliovirus) • Negri bodies (rabies virus) Viral proteins have ‘addresses’ built into their structure • Membrane targeYng: Signal sequences, fa\y acid modificaons • Membrane retenYon signals • Nuclear localizaYon sequences (NLS) • Nuclear export signals 414 Localiza3on of viral proteins to the nucleus CHAPTER 12 Golgi apparatus Ribosome Rough endoplasmic reticulum Plasma membrane Py(VP1) + VP2/3 Ad hexon + 5 100 kDa Nuclear envelope: Outer nuclear membrane Inner nuclear membrane Nucleus Nuclear pore complex Mitochondrion Cytoskeleton: Influenza virus NP Intermediate filament Microtubule Actin filament bundle Extracellular matrix ©Principles of Virology, ASM Press Figure 12.1 Localization of viral proteins to the nucleus. The nucleus and major membrane-bound compartments of the cytoplasm, as well as components of the cytoskeleton, are illustrated schematically and not to scale. Viral proteins destined for the nucleus are synthesized by cytoplasmic polyribosomes, as illustrated for the infl uenza virus NP protein. They engage with the cytoplasmic face of the nuclear pore complex and are translocated into the nucleus by the protein import machinery of the host cell. Some viral structural proteins enter the nucleus as preassembled structural units (polyomaviral [Py] VP1 pentamers associated with one molecule of either VP2 or VP3) or in association with a viral chaperone (adenoviral [Ad] hexon monomers bound to the L4 100-kDa protein). polyomaviruses, must enter the nucleus despite continual Assembly of the heteromeric complex facilitates import of transport of cellular proteins. Whether import of viral pro- the minor structural proteins, even though each contains teins is favored in such circumstances, for example, by the a nuclear localization signal. The increased density of these presence of particularly effective nuclear localization sig- signals may allow more effective competition for essential nals, is not known. components of the import pathway, or the nuclear local- Many viral structural proteins that enter infected cell ization signals may be more accessible in the complex. nuclei form multimeric capsid components. In some cases, Despite such potential advantages as increased effi - structural units of the virion are assembled in the cyto- ciency of import of viral proteins and transport of the struc- plasm prior to import into the nucleus. Pentamers of the tural proteins in the appropriate stoichiometry, import of major capsid protein (VP1) of simian virus 40 and poly- preassembled capsid components is not universal. For omavirus specifi cally bind a monomer of either VP2 or example, adenoviral hexons, which are trimers of viral VP3, the minor virion proteins, which share C-terminal protein II, are found only in the nucleus of the infected sequences (Appendix, Fig. 15B). Such heteromeric assem- cell. Association of newly synthesized hexon monomers blies are the substrates for import into the nucleus. Indeed, with a late, nonstructural protein, the L4 100-kDa protein, effi cient nuclear localization of polyomavirus VP2 and VP3 is essential for both the entry of hexon subunits into the proteins occurs only in cells in which VP1 is also made. nucleus and their assembly into trimers. The monomeric AASM-FLINT-08-0601-C012.inddSM-FLINT-08-0601-C012.indd 441414 99/12/08/12/08 44:58:00:58:00 PPMM Intracellular Traffi cking 415 hexon-L4 protein complex must be the import substrate. Transport of Viral Membrane Proteins The viral L4 100-kDa protein might supply the nuclear to the Plasma Membrane localization signal for hexon import, or promote nuclear Viral membrane proteins reach their destinations by the retention, by facilitating assembly of hexon trimers within highly conserved, cellular secretory pathway. Many of the nucleus. the steps in the pathway have been studied by using viral membrane glycoproteins, such as the vesicular stomatitis Assembly at the Plasma Membrane virus G and infl uenza virus hemagglutinin (HA) proteins. Assembly of enveloped viruses frequently takes place at the These viral proteins offer several experimental advantages: plasma membrane of infected cells (Table 12.1). Before such they are frequently synthesized in large quantities, their virions can form, viral integral membrane proteins must be synthesis is initiated in a controlled fashion following infec- transported to this cellular membrane (Fig. 12.2). The fi rst tion, and their transport can be studied readily by genetic, stages of the pathway by which viral and cellular proteins biochemical, and imaging methods. are delivered to the plasma membrane were identifi ed more Entry into the fi rst staging post of the secretory path- than 30 years ago, and the process is now quite well under- way, the endoplasmic reticulum (ER), is accompanied by stood. Viruses with envelopes derived from the plasma membrane insertion of integral membrane proteins. Viral membrane also contain internal proteins, which may be envelope proteins generally span the cellular membrane membrane associated, and, of course, nucleic acid genomes. into which they are inserted only once, and therefore con- These internal components must also be sorted to appropri- tain a single transmembrane domain. In viral proteins, ate plasma membrane sites for assembly (Fig. 12.2). transmembrane segments (described in Chapter 5) usually Figure 12.2 Localization of viral proteins to the plasma membrane. Viral envelope glycoproteins (red) are cotranslationally translocated into the ER lumen and folded and assembled within that compartment. They travel via transport vesicles to and through the Golgi apparatus and from the Golgi apparatus to the Localiza3on of viral proteins to plasma membraneplasma membrane. The internal proteins of the particle (purple) and the genome (green) are also directed to plasma membrane sites of assembly. Other viral Viral RNA Nascent viral protein proteins Cell surface viral protein Golgi Fusion Nucleus Transport vesicle Mitochondrion Microtubule ER Cytoskeleton Extracellular matrix ©Principles of Virology, ASM Press AASM-FLINT-08-0601-C012.inddSM-FLINT-08-0601-C012.indd 441515 99/12/08/12/08 44:58:00:58:00 PPMM Three strategies for making sub-assemblies ©Principles of Virology, ASM Press viral chaperone ©Principles of Virology, ASM Press Sequen3al capsid assembly: Poliovirus ©Principles of Virology, ASM Press Assembly intermediates and the assembly-line concept • Ensure orderly formaon of viral parYcles and virion subunits • FormaYon of discrete intermediate structures • Can’t proceed unless previous structure is formed: quality control ©Principles of Virology, ASM Press {sequenYal} Viral scaffolding proteins • establish transient intermediate structures • viral proteases packaged in these intermediate structures become acYvated to finalize structure ©Principles of Virology, ASM Press Sequen3al Assembly Adenovirus genome packaged into a preformed shell in the nucleus ©Principles of Virology, ASM Press Self-assembly vs assisted assembly reacons • Self-assembly - Retrovirus gag, influenza HA, HBV surface form VLPs • Assisted assembly - Can’t assemble alone - Proteins and genomes required as scaffolds or chaperones to form structure Concerted Assembly Influenza virus parYcles form by budding ©Principles of Virology, ASM Press ©Principles of Virology, ASM Press ©Principles of Virology, ASM Press Genome packaging • Problem: Viral genomes must be disYnguished from cellular DNA or RNA molecules where assembly takes place • Soluon: Packaging signals in the viral genome Packaging signals - DNA genomes ! Adenovirus • Packaging signal near leS inverted repeat and origin • Signal is complex: a set of repeated sequences; overlapping with enhancers that sYmulate late transcripYon • Recognized by viral protein IV2a (also a transcripYonal acYvator) ©Principles of Virology, ASM Press •Herpesvirus genome replicaYon produces concatemers with head-to-tail copies of viral genome ! •HSV-1 packaging signals pac1 and pac2 needed for recogniYon of viral DNA and cleavage within DR1 ©Principles of Virology, ASM Press Packaging signals - RNA Necessary but not sufficient for HIV-1 genome packaging ©Principles of Virology, ASM Press Packaging signals - RNA genomes 350 nt env mRNAs not packaged ©Principles of Virology, ASM Press Packaging of segmented genomes • Random mechanism would yield 1 infecYous parYcle per 400 assembled - within known parYcle:pfu raYo • Evidence for specific packaging sequence on each RNA segment Influenza virus RNA packaging h\p://www.virology.ws/2009/06/26/packaging-of-the-segmented-influenza-rna-genome/ Selec3ve packaging • Bacteriophage ϕ6 - 3 dsRNA segments S, M, L • Serial dependence of packaging: S-M-L • ParYcle:pfu raYo ~1 Acquisi3on of an envelope • Aer assembly of internal structures (most enveloped viruses) • Simultaneous with assembly of internal structures (retroviruses) Four budding strategies Envelope Internal
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