Viral Fusion Proteins

Greetings

      I have been recently listening to some of the fantastic seminars on basics of viral replication (You can get them on Youtube!!). And one of the seminars that was pulling me through and got me thinking was about a virus gaining entrance to a cell. That lead me to gather and seek information on viral fusion proteins. Thought, that would make a excellent blog topic.

    Viruses are cell specific. They don't get into each and every cell type they had encounter. Fidelity is an important part of replication, as the cell type determines the further progress of the viral life cycle. A virus ending up inside a wrong cell is as good as a dead end. The virus thus has machinery designed to determine the right receptor (and hence the right cell). Viral fusion proteins, that serve this purpose, is a simple elegant machinery that mediates Cell-virus fusion and hence represents a great potential as a therapy target.

    A wide variety of viral fusion proteins (Henceforth referred in this post as fusion proteins), is known with a great variety of sequences, and diverse triggering and activation mechanisms. Structurally almost all, have a trimeric structure which mediates membrane binding and subsequent fusion of 2 membranes as I have shown here in Fig 1. The figure described below is not to scale or accurate. However, it conveys the concept. The basic idea is that the fusion protein pulls the two membrane close together via a spring load type or a hairpin type mechanism, finally culminating in membrane fusion. You get the idea.

Fig 1: Basic concept of virus membrane fusion.

Table 1: Viral Fusion proteins

       Based on the detailed structure and the exact mechanism of fusion, these fusion proteins are classified into 3 types- Class I to III. The most important contrasts between the 3 types are shown in Table 1. The fusion proteins are usually present in an inactive form. On contact with a specific receptor or by factors such as pH (Or some times both), they are processed and converted to an active form.

        High resolution details are available for various different fusion proteins. The details are not so important. I will give a very general idea of the events.

      Viruses such as Influenza are endocytosed by the cells. The endosomal compartment inserts proton pumps (via natural process or sometimes through viroporins) and hence there is a resulting change leading to acidification. Changes in pH can lead to significant conformational changes in the 3D- structure. In case of Influenza the hemagglutinin globular head domains is clipped off and clamps the fusion subunit in its pre-fusion state binds the membranes. Then as already discussed above, the fusion protein fuses the outer membrane of the virus with inner membrane of endosomal compartment which helps in nucleic acid escape. Wait a minute, is there a sensor? Oh yes, amino acid like histidine with good protonation capacities can serve as excellent sensors. This is one of the classic example of Class I pH activated fusion. This however, seems to be a little bit of problem. If u acidify (say for example) an artificial liposomal membrane,  the virus has no way to know and you still get the release which is a wasted process. This problem has been overcome by use of specific receptors which can modulate pH dependence.

Table 2: Examples of virus under different class

          Class II proteins are structurally unrelated to class I. They lie parallel to the viral membrane with fusion component buried inside and thus protected. In contrast Class I was fusion ready, but had to be activated by unmasking a fusion competent residue. In Class II, the trigger system (pH, receptor, specific enzymes, chaperones etc) causes conformational change and subsequent rotation of the structure which ends up as a parallel fusion protein. The subsequent events are the same as in Class I.

     Class III proteins are more recently discovered type that has characters of both classes. The virus commonly studied in this class is Rhabdoviridae and Herpesviridae. The mechanism of action is similar to what is already discussed. The specialty of these type is that pre-fusion and post-fusion states are in equilibrium, and it can be shifted to any side depending on condition such as pH. That means they can switch on and off (reversible). Whereas in class I and II the action is not reversible.

  The reason why we have been son interested is that fusion inhibitors are an excellent mode of antivirals. HIV fusion inhibitors were developed by creating analogues of the fusion machinery which blocks the machinery and therefore viral nucleic acid injection is prevented. We can also trick the virus by using triggers and thereby confusing the virus to eject nucleic acid in a blank environment. That is the basic idea of "DAVEI" (Dual Action Virolytic Entry Inhibitor) (Link). The influenza ferret story (Link), that was heavily debated for its possibility of dual use research was actually aimed at finding the key amino acids in the structure that allows fusion trigger.

   In conclusion, viral fusion is a series of protein thermodynamics events which provides a trimer- hairpin structure that can pull the two membranes sufficiently close so, as to cause fusion.

Kielian M, & Rey FA (2006). Virus membrane-fusion proteins: more than one way to make a hairpin. Nature reviews. Microbiology, 4 (1), 67-76 PMID: 16357862

Judith M. White, Sue E. Delos, Matthew Brecher, and Kathryn Schornberg (2008). Structures and Mechanisms of Viral Membrane Fusion Proteins. Crit Rev Biochem Mol Biol. 43(3): 189–219. PMCID: PMC2649671