Biology Reference
In-Depth Information
In fact, the matrix proteins of filoviruses and rhabdoviruses, as well
as the Gag proteins of several retroviruses, contain small, conserved
motifs that are recognized by cellular proteins involved in protein-
sorting and transport.
33,58,59
These motifs are called “late domains”
to reflect their function late in the viral lifecycle. To date, three
late-domain motifs have been described: P(T/S)AP, PPXY, and
YXXL.
The PPXY motif interacts with the WW domain of Nedd4-like E3
ubiquitin ligases,
16,26-28
resulting in mono-ubiquitination of the cargo
protein and its recognition by the endosomal sorting machinery. The
P(T/S)AP motif is recognized by Tsg101,
28-30
a component of the
ESCRT-I (endosomal sorting complex required for transport) com-
plex. The YXXL motif binds to two proteins, AP-2
31
and AIP1.
32,33
AP-2 is involved in endocytosis, whereas AIP1 interacts with a com-
ponent of the ESCRT-III complex.
The Marburg virus VP40 protein contains a PPXY motif near its
amino-terminus, whereas the Ebola virus VP40 protein is character-
ized by overlapping PTAP and PPXY motifs (PTAPPEY at amino acids
7-13).
16,34
Extensive
in vitro
characterization of VP40 proteins con-
taining mutations or deletions in their late domains has indicated that
both domains play a role in virus budding.
6,16,35,36
However, reverse
genetics allowed the artificial generation of Ebola viruses with muta-
tions in one or both late-domain motifs.
55
The resultant mutant viruses
were only mildly to moderately attenuated in cell culture, demonstrat-
ing that the late domains are not absolutely required for Ebola virus
replication in cell culture. However, they are likely needed to achieve
optimal replication efficiencies.
Many viruses contain two late-domain motifs separated by only a
few amino acids (the Ebola virus VP40 protein is an exception in that
the late domains overlap). While the late domains were originally
thought to be functionally interchangeable and thus redundant, more
recent data suggest that both motifs are required for efficient particle
formation.
58
The two late domains may trigger sequential steps in
which recruitment of Nedd4-like ubiquitin ligases (mediated by the
PPXX motif) results in the ubiquitination of the cargo protein. The
ubiquitinated cargo protein may then have an increased affinity for
