Retroviral Envelope Glycoproteins: Structure and Evolution.
Abstract: Among the
five retroviral genera with Class I viral fusion proteins (lentiviruses and the alpha-,
beta-, gamma-, and deltaretroviruses) are found either of two mechanisms of Env subunit
association - covalent association mediated by disulfide bonding between cysteines, or
noncovalent interactions among various residues at the SU/TM interface. The nature and
strength of the associati... read moreon and subsequent dissociation of the SU and TM subunits are
important in ensuring that critical regions of Env are exposed for the briefest time
possible during receptor binding and fusion, when retroviral Env proteins are vulnerable
to neutralizing antibodies produced by the host organism. Env subunit association
remains uncharacterized in the Betaretrovirus genus. This genus includes Jaagsiekte
sheep retrovirus (JSRV) and mouse mammary tumor virus (MMTV)--both of which are
pathogenic--as well as many endogenous retroviruses, including the HERV-K(HML2) family
that has proliferated in the primate lineage over a period of more than 30 million
years. We undertook to determine the nature of the subunit association in betaretroviral
Env proteins and discovered that they share with lentiviruses an Env structure with
noncovalently associated subunits. The lack of covalent bonding in the Env proteins of
these two genera correlates with the lack of a particular cysteine in the TM ectodomain,
as well as a couple of other TM sequence features that allow easy distinction between
the two TM types--lack of an immunosuppressive domain (ISD) and a longer membrane
proximal external region (MPER). We took advantage of these sequence features to screen
the NCBI genomic databases for TM sequences of each type, hypothesizing that the
structural difference associated with the two TM types would have implications for host
range that had been overlooked in the previous surveys based on the pol gene. Indeed,
our survey results showed a sharp distinction in host range between the two TM types.
While retroviruses with covalent type Env can cross multiple taxonomic boundaries,
noncovalent types are limited to mammals. This TM-based approach also allowed us to
identify a novel recombinant retrovirus in the genome of the white-throated sparrow,
underscoring the importance of recombination in creating diversity and expanding host
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Molecular Microbiology.
Advisor: John Coffin.
Committee: Ekaterina Heldwein, Naomi Rosenberg, and Abraham Sonnenshein.
Keywords: Virology, and Molecular biology.read less