Class I and II Fusion Proteins

1
Class I and II Fusion Proteins

• To reproduce, enveloped viruses must enter a host
  cell by fusing their own membrane coat with that
  of the cell.
• Fusion is caused by specific proteins in the
  viral membrane, and at least two classes of these
  proteins have been identified.
• In both classes, tightly regulated conformational
  changes are involved in membrane fusion.

2
Class I Fusion Proteins

• Class I fusion proteins are composed of three
  identical protein subunits, the functional forms
  of which are generated from a precursor that is
  cleaved into two pieces. The carboxy-terminal end
  of one piece is anchored to the viral membrane
  the other end (the new amino terminus) has a
  characteristic stretch of 20 hydrophobic amino
  acids the fusion peptide.
• An essential feature of class I proteins is the
  formation of a trimeric helical coiled-coil rod
  adjacent to the fusion peptide. This structure
  may act as a template for the refolding of
  protein segments near to the segments anchored in
  the virus membrane.

3
Class I Flu, HIV, Paramyxo
4
Class I Fusion Proteins

• After binding to a receptor on the cellular
  membrane, or on exposure to the low pH found in
  intracellular compartments (endosomes), the
  protein forms an extended conformation and the
  hydrophobic fusion peptide inserts into the
  target membrane.
• Several trimers are thought to be involved.
• Protein refolding begins. The free energy thereby
  released causes the membranes to bend towards
  each other.
• Formation of a restricted hemifusion stalk allows
  the lipids in the outer leaflets of the membranes
  to mix.
• Protein refolding completes, forming the final,
  most stable form of the fusion protein,with the
  fusion peptide and transmembrane domain
  anti-parallel to each other but in the same
  membrane.

5
Class II Fusion Proteins

• Class II fusion proteins have distinctly
  different structural features they are
  predominantly non-helical, instead having a
  ß-sheet-type structure they are not cleaved
  during biosynthesis and the portion that inserts
  into the target membrane is thought to be an
  internal hydrophobic fusion loop.
• The proteins have a three-domain architecture, in
  which domain I begins at the amino terminus,
  domain II contains the internal fusion loop, and
  domain III is at the carboxy terminus

6
Class II Dengue, Tick-Borne Encephalitis,
Semliki Forest Viruses
7
Class II Fusion Proteins

• The dimeric E protein binds to a cellular
  receptor and the virus is internalized to
  endosomes.
• The acidic pH inside endosomes causes domain II
  to swing upward, permitting E monomers to
  rearrange laterally.
• The fusion loop inserts into the outer leaflet of
  the host-cell membrane, enabling trimer
  formation.
• The formation of trimer contacts extends from the
  top to the bottom of the molecule. Domain III
  shifts and rotates to create contacts, bending
  the membrane.
• The formation of further contacts leads to
  unrestricted hemifusion and the final most stable
  form of the protein.