lecture 2 viral genomes, proteins, lipids dinman
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Lecture 2 BSCI437. VIRAL GENOMES,
PROTEINS, AND LIPIDS.
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Criteria for viral genomes
• Must use same genetic code as host • Must use same biomolecules as host:
Nucleic Acids. Proteins, carbohydrates and lipids.
• Modifications (polyadenylation of mRNA, capping, splicing) must either depend on viral enzymes or host enzymes
• Continuous pressure to minimize size• Fast replication (especially important
in bacteria where virus must keep up with host)
• Genome packaging. – It takes a capsid of several million Daltons
to package a 10 kb genome. – The larger the genome the larger the
capsid must be and this means more energy and time required for synthesis).
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All varieties of genomes
– (+) ssRNA– (-) ssRNA– dsRNA– retrovirus (+ssRNA dsDNA)– ssDNA– dsDNA– Mixed DNA and RNA
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Thymidine tautomers
Basepairs with Adenine
Basepairs with Guanine
10-4
104
Tautomerization of pyramidines: the primary chemical basis for mutagenesis.
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Tautomerization of pyramidines: Cytosine tautomerization is an order of
magnitude less.
Basepairs with Guanine
Basepairs with Adenine
10-5
105
H
Enamine Enimine
Cytosine tautomers
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Properties of viruses relative to genome
type
• Size Range: Range from encoding as little ≈2 kb (Circoviruses), to as large as 800 kb (Mimiviruses)
• Variations (single molecule or segmented)
• NTP Polymerases: Viral or host origin
• Fidelity of replication – From high fidelity (<10-9/nt) to
low fidelity (10-4/nt)
• Recombination• Reassortment
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Genome topologies
Includes every possible combination of: • double stranded or single stranded, • linear or circular, • contiguous, segmented, or gapped• polarity: Single stranded (+) strand, (-) strand, or
ambisense
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Structure & Composition of Genomes: Generally, any and all possible combinations are
known.
Composition. Can be RNA, DNA, and/or any combination thereof!
•DNA or RNA•DNA with short RNA segments•DNA or RNA with covalently attached protein (e.g. polio)
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Cicrcular ds DNA genomes
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Linear dsDNA genomes
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Linear dsDNA genomes
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Gapped circular dsDNA genomes
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Circular ssDNA genomes
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dsRNA genomes
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(+) ssRNA genomes
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(+) ssRNA with DNA intermediate
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Linear (-) ssRNA genomes
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Segmented (-) ssRNA genomes
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Ambisense ssRNA genomes
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Special properties
• Terminal Redundancy: genomes of many viruses are terminally redundant. Used as tools for replication, expression, integration into host chromosomes, and for protection of ends. Examples include λ, retro-, adeno-, parvo-, pox-, bunya-, and arenaviruses.
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Special properties
• Covalent Modifications: Includes modifications to nucleic acids (eg. methylation, pseudouridylation, etc.), and covalent linkage with proteins. Of the latter, proteins covalently linked to the 5' ends of picorna- and adenoviruse RNAs play important roles in cap-independent translation.
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Genome condensation
strategies• Hijack host proteins for some
or all replication functions• Overlapping genes • Genes on both strands of
dsDNA in opposite directions• Multiple splicing of the same
transcript to make many different proteins (only need 1 promoter)
• Polyprotein production from one mRNA and subsequent proteolytic cleavage
• Frameshift mechanisms allow downstream out of frame genes to be made at appropriate proportions
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Viral adaptation and evolution through
mutation
• Three major phenomena are used:1. Base misincorporations by
polymerases.2. Recombination by breakage
and religation in all DNA viruses or RNA viruses with a DNA intermediate or by Copy-choice with many ssRNA viruses.
3. Reassortment in the case of viruses with multipartite genomes (more than one segment)
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Mutation• Viruses are subject to the same type of
mutations as other organisms: – Transitions and transversions – Deletions – Insertions – Nonsense mutations.
• Mutations can be spontaneous or induced. – Inducing agents commonly used to directly
mutate the virus for study.– Mutations can be used to map genes in viruses
just as they are used to map in bacteria. • Mutations are also useful in determining
the function of a protein. – Conditional mutants- a mutant phenotype that is
replication competent under “permissive” but not “restrictive” or “nonpermissive” conditions.
• Mutations are subject to reversion either at the same or a different (pseudorevertant) location in the genome.
• Mutants can also be complemented by other viral strains in a superinfection.
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Genome related phenomena
• Reassortment: exchange of genome segments in segmented viruses. e.g. Influenza
• Transduction: Incorporation of host cellular genes into viral genome, e.g. RSV
• Attenuation: virulence lost but virus can still replicate in host.
• Recombination: Exchange of genetic information between two or more virus genomes.
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Non-Genome related
phenomena• Interference: inhibition of
replication or infection of one type of virus by another. e.g. HIV-1 prevention of CD4 expression in infected cell; Defective Interfering Particles in plant viruses.
• Phenotypic mixing: exchange of envelopes or coat proteins between different viruses. “Pseudotypes”
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Viral ProteinsAs few as 2 and as many as >50 virus-encoded
proteins. Generally divided into “Structural” and “Non-structural”.
• Structural: These compose the capsids/nucleocapsids, and envelope proteins. – Primary function of those involved in
capsid/nucleocapsids is to serve as building blocks for the virion (viral particle).
• Envelope proteins are typically glycoproteins in the form of spikes or projections. – Typically, these serve as receptors for host cell-
surface glycoproteins and are involved in viral attachment and entry into cells (infection).
• Non-structural: proteins with enzymatic, virus replicative, or for interactions with host-cell encoded factors. – Examples from HIV include Pol, Int, RNase H,
Integrase, Nef, Vif, and Tat.
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Viral Lipids
• Viral envelopes contain complex mixtures of neutral lipids, phospholipids and glycolipids.
• As a rule, their composition resembles that of the host cell membrane from which the envelope was derived.
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Host-encoded molecules
• Viruses can pick up molecules from host cells.
• Lipids. – Make up bulk of viral
envelopes. – Taken from host cellular
membranes.
• RNAs. – tRNAs used for priming. – 5S rRNA and other trans-
acting factors used in translation initiation.