1 within a species (mutations frequent lead to

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Last updated: May 18, 2019

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1.Fusion Peptides(FPs) Viruses are infectious agents that replicates onlywithin the cells of living hosts, mainly bacteria, plants, and animals. They’reusually composed of an RNA or DNA core, a nuclear membrane, and, in morecomplex types, a surrounding envelope (plasma membrane).

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Enveloped viruses(e.g. influenza, HIV, Dengue) have viral envelopes covering their geneticmaterial and typically derive from portions of the host cell membranes(phospholipids and proteins), including some viral glycoproteins. Glycoproteinson the surface of the envelope help identifying and binding to receptor siteson the host’s membrane, inducing membrane fusion, allowing the viral genome toenter and infect the host. This process is collectively known as “viral entry”1, 2 and although it seems like it, this mechanism is not simple andthere are significant differences among different viruses2.Despite glycoproteins induce membrane fusion, researchers believethat it’s a small portion that triggers the whole mechanism – the fusion peptide.

This peptide segment has membrane -perturbing activity and cause fusionproteins’ irreversible conformational changes during viral fusion 3.All FPs share common characteristics, which aredeterminant for their function: they are hydrophobic, rich in Gly and Alaresidues, contain aromatic residues and are usually conserved within a species(mutations frequent lead to a loss of function).4, 5 Apart from these general characteristics, FPs from virus belongingto different families can be quite diverse 4. Some FPs (e.g. Influenza and HIV) are located at the N-terminaltip of the fusion protein, whereas the peptides of other viruses (e.g. dengueand Ebola) are internal fusion loops 4.

The peptides from different families are also quite different atthe sequence level and structure levels. The influenza FP is helical in lipidicenvironments 6, 7, whereas the HIV FP tends to adopt ?-sheet structures8, although it can become helical depending on membrane composition9. Other FPs, such as the one from dengue virus, which only has 14residues, do not have a defined secondary structure10. It is not clear how peptides with such distinct characteristicsplay a common role in membrane fusion. 1.2. Viral Entry ExplainedMany fusion proteins are C-terminal fragments of alarger precursor (eg: HA2 fragment of influenza virus hemagglutinin; gp41fragment of HIV Env)3 and the mechanism by which fusion proteins mediatemembrane fusion is a complex process that involves several segments of theseproteins. First the fusion protein opens up and forms a bridge between the twobilayer membranes.

Usually a C-terminal transmembrane region holds the fusion proteinin the membrane for the fusion peptide (located ate the N-terminal fragment ofthe fusion protein or internally – fusion loops – depending on the virus) couldconnect and interact with the viral membrane. This interaction possibly makesthe fusion protein undergo many conformational changes until the bridgecol-lapses resulting in a junction of the fusion peptide and the C-terminalfragment, creating a fusion pore.3 Figure 1 Schematicrepresentation of the sequence of events in membrane fusion promoted by a viralfusion protein.

(a) The protein in the pre-fusion conformation, withits fusion peptide or loop (light green) held. Some features of specificproteins are not represented (eg: displacement of the N-terminal fragment ofproteins that are cleaved from a precursor or the dimer-to-trimer rearrangementon the surface of flaviviruses). (b) The protein opens up, extending the fusion peptideor loop to interact with the target bilayer. The part of the protein that bearsthe fusion peptide forms a trimer cluster. (c) A C-terminal segment of the protein folds backalong the outside of the trimer core.

The segments from the three subunits foldback independently, so that at any point in the process they can extend todifferent distances along the trimer axis, and the entire trimer can bowoutward, away from the deforming membrane. (d) When collapse of the intermediate has brought the two bilayers into contact, proximalleaflets merge into a hemi-fusion stalk. (e) As the hemifused bilayers open into a fusion pore,the final zipping up of the C-terminal segments breaks the refolded trimer intoits fully symmetric, post-fusion conformation, preventing the pore fromresealing 3.

 There are at least four distinctmechanisms (eg.: pH, binding to another surface protein, temperature or fusionprotein cleavage) by which viral fusion proteins can be triggered to undergofusion inducing conformational changes 11. Despite thisdiversity, all characterized viral fusion proteins convert from afusion-competent state (dimers or trimers, depending on the class) to amembrane-embedded homotrimeric prehairpin, and then to a trimer-of-hairpins.Additionally, all fusion proteins contain a fusion peptide (FP), which insertsinto the host membrane during fusion.Three distinct classes of viral fusionproteins have been identified based on structural criteria.

Class I fusion proteins, observed in influenzavirus, HIV and SARS virus, are characterized by a trimeric assembly of ?-helical coiled coil hairpins in the post-fusion stateFigure 2.2 These fusion proteins usually require proteolyticprocessing into two subunits (e.g., influenza HA, paramyxovirus F), for someviruses (e.g., Ebola virus GP) processing into the two subunits occurs for thewt protein, but is not essential for infection 12.

Some coronavirus S precursorsare (e.g., MHV), whereas others (e.g., SARS) are not, proteolytically processedduring biosynthesis. These latter coronaviruses S proteins as well as for Ebolavirus GP and Hendra and Nipah virus F, may be substituted by post syntheticcleavage by extracellular or intracellular (e.g.

, endosomal cathepsins)proteases 13They are characterized for being metastable on thevirion and perpendicular (project as a spike) to the viral membrane. The majorsecondary structure of the native fusion subunit is ?-helical, and the oligomeric structure is a trimer as well as the oligomericstructure of fusion-active form (membrane-embedded prehairpin and bundles),however, the structure of the post-fusion form is a trimer-of-hairpins (central?-helical coiled-coil, 6HB in figure1 iv).In class I native fusion proteins the fusion peptide is buried in the subunitinterface, whereas in the primary sequence this fusion peptide is located at ornear the N-terminus 14.Onthe other hand, class II fusionproteins, found in flaviviruses and alphaviruses, are categorized as trimers ofhairpins composed of ?-sheets in the postfusion state Figure 3.  15  These class II fusion proteins consist primarily of ?-sheet structure with internal fusion peptides formedas loops at the tips of ?-strands.

They areassociated with a chaperone protein (p62 for SFV E1 and prM for TBEV E), whichis cleaved during or soon after viral assembly so that the fusion proteingenerates a competent form. Similarly to class I fusion proteins, class IIFProt are also metastable on the virion, however, unlike class I, these classII orientation is parallel (close to) the viral membrane. Their native fusionprotein oligomeric structure are dimers, whereas the oligomeric structure ofthe fusion-active form (membrane – embedded prehairpin and bundles) is atrimer, and the structure of the post-fusion form is a trimer of hairpins(mainly ?-structure).In the native fusion protein, the FP is masked in the trimer interface, at thetip of the extended ?-strands, and itslocation in a primary sequence is internally.

14   A class III fusion protein, found in vesicularstomatitis virus and herpes simplex virus, is also characterized by trimers ofhairpins although formed by the helical coiled-coil and ?-sheets structures. 2 The pre-fusion form ofVSV G is a trimer, but the trimer interface is small. In contrast to those inthe pre-fusion conformations of all other fusion proteins known to date, thefusion loops (red) are located on the outside of the structure, not protectedat an interface. Upon acidification, a series of conformational changes occurin VSV G that reposition the fusion loops (red) into the vicinity of the targetmembrane.

A second series of conformational changes then bend the protein back,reorienting the C-terminal portion anti-parallel to the N-terminal segment,thereby bringing the viral and target membranes together. (see Figure 4). Figure 4 Crystalstructures of the neutral (i and ii) and low pH (iii and iv) forms of the VSV Gectodomain.In the first step, conformationalchanges occur in two regions, Ex1 and Ex2 (orange in i, ii, and iii). Each region has two parts, oneis an unstructured linker, the other has helical structure. During theconformational change the unstructured linker of Ex1 becomes helical and thehelical residues become unstructured, resulting in movement of the fusiondomain (DIV) approximately 90°. The motion of DIV is completed by changes inEx2, in which linkers between DII (blue-gray in ii) and DIII (cyan), become helical, extending each of the two DII helices (blue-grayand orange in iii). The result isthe rotation of both DIII and DIV such thatthe fusion loops (red) are now near the target membrane.

Finally,inversion of the C-terminal stem is accomplished by additional structural rearrangementsin Domain II. In particular, an unstructured loop (Inv, greenin ii) becomes an ?-helix, which we refer to in Figure 6D as the “C-helix” (green in iii),that is oriented antiparallel to the core structure. Consequently, the”C-helix” packs against the now elongated helix of Domain II (blue-grayand orange in iii), bringing theC-terminus and viral membrane into proximity with the target membrane, therebyfacilitating fusion.14 Class III G fusion proteins’ conformational changes ofsome rhabdovirus are hypothesized to be reversible (Gb fusion protein it’sstill unknow) since the pre-fusion and post-fusion states are in thermodynamicequilibrium, with the equilibrium shifted towards the post fusion state at lowpH 16, unlike the majorityof other viral fusion proteins, which are metastable and irreversiblyinactivated (lose the capacity to mediate fusion with a subsequently presentedtarget membrane) if triggered in the absence of a target membrane. Also, thesefusion proteins don’t require proteolytic processing to generate a fusion ableform, and are perpendicularly orientated towards the viral membrane. Theoligomeric structure of the fusion protein’s native form it’s a trimer as wellas its fusion-active form (membrane-embedded prehairpin and bundles), while thepost-fusion structure is a trimer of hairpins (central ?-helical coiledcoil and significant ?-structure). Regarding the fusion peptide’s location, in the native formit’s exposed at the tips of the extended ?-strands, whereas in primary sequence it’s located internally, containingtwo loops found at the tips of two neighboring ?-strands.

The fusion peptide (FP) is one of the most relevantplayers in the fusion process, 11 this segment of thefusion protein inserts in the host membrane and has an active role in promotingfusion. The FP is a very promising drug target, since it is conserved within aviral species and is vital for the infection process (e.g. antibodies againstdengue virus target this region 4, 17).

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