|
Sheila Baker, Ph.D.
"I am pleased
to be a part of the molecular vision training program.
This will provide me with an excellent opportunity to interact
with respected leaders in the various aspects of vision science
and better prepare me for a career as an independent investigator."
The ability of the visual phototransduction
cascade to rapidly activate and subsequently deactivate provides
the molecular foundation that allows animals to process and
adapt to environments full of moving objects and changing
light intensities. A central player in the phototransduction
cascade is the heterotrimeric G-protein, transducin.
Transducin transmits information between the light activated
receptor, rhodopsin, and the effector, cGMP phosphodiesterase
(PDE). Transducin is activated by rhodopsin via the
exchange of GDP for GTP and then deactivated when it hydrolyzes
the bound GTP. However, the intrinsic rate of transducin's
GTPase activity is too slow to account for the rapid deactivation
that occurs physiologically. To overcome this problem,
the GTPase activity of transducin is dramatically enhanced
by the RGS9·Gb5 complex. RGS9 is composed of multiple
discrete domains, including a DEP (Disheveled/EGL-10/Pleckstrin
homology) domain which mediates the interaction between RGS9
and its membrane anchor protein, R9AP. This interaction
contributes to three distinct aspects of RGS9·Gb5 regulation.
It is absolutely required for the delivery of RGS9·Gb5
protein to the outer segment of the photoreceptor. Once
in the outer segment, RGS9 is tethered to the membrane by
R9AP so that it is held in close proximity to transducin.
Finally, this interaction greatly enhances the ability
of RGS9 to activate transducin GTPase. Relatively little
is known about R9AP, even though it plays such an important
role in the RGS9·Gb5 signaling complex. R9AP
is a membrane protein containing a single C-terminal transmembrane
domain. However, the mechanism of the interaction between
R9AP and the DEP domain of RGS9 is not known. An important
clue comes from the recent analysis indicating that R9AP shares
considerable homology to syntaxin and other members of the
SNARE protein family involved in vesicular trafficking and
membrane fusion. Based on its similarity to SNARE proteins,
R9AP is predicted to fold into a series of coiled-coil domains,
one or more of which may bind RGS9. The goal of our
current work is to define the molecular interactions between
R9AP and RGS9-1 as this will help us uncover exactly how this
signaling complex functions.
|
