Domain structure of GRK2. The Gβγ subunits have been
omitted from the figure for clarity.
The structure of the GRK2–Gβγ complex is the first
that has been determined of any member of the GRK family and the
first of any effector enzyme targeted by Gβγ. The three
GRK2 domains [the RGS homology (RH), protein kinase, and PH domains]
are arranged such that they form a triangular shape approximately
80 Å on a side. The "membrane proximal" surface
of the triangular GRK2–Gβγ complex is positively
charged and flat, suggesting that it is this surface that interacts
with the negatively charged plasma membrane. This surface also includes
the phospholipid binding loop in the PH domain and the geranylgeranyl
group of Gγ that tethers Gβγ to the plasma membrane
in cells.
Model of GRK2 in complex with G proteins and a GPCR. A GPCR (red)
and Gαq (teal) have been docked with
the GRK2–Gβγ complex. This configuration would
efficiently shut down GPCR-mediated signaling by inactivating
the receptor at the same time as it sequesters the G proteins
that the receptor itself activated.
The interdomain contacts of GRK2 fix the orientations of its three
domains at the membrane surface such that each can perform a discrete
desensitizing task. The kinase active site cleft faces the cell
membrane where GPCRs are found; the PH domain is oriented to allow
its interaction with Gβγ and phospholipid head groups;
and the RH domain is positioned such that it can sequester an activated
Gα subunit. Furthermore, Gβγ, Gα, and GPCR binding
sites are found at unique vertices of the GRK2 triangle, suggesting
that GRK2 can bind all three proteins at the same time. This configuration
allows for the rapid attenuation of the signal that was propagated
by the activated GPCR; thus the GPCR can be desensitized by phosphorylation
while the free Gβγ and Gα subunits are blocked from
activating their downstream signaling cascades.
Research conducted by D.T. Lodowski and J.J.G. Tesmer (University
of Texas at Austin), J. A. Pitcher (University College London),
and W.D. Capel R.J. Lefkowitz (Howard Hughes Medical Institute and
Duke University Medical Center).
Research funding: American Heart Association (Texas and National
affiliates), Welch Foundation, Research Corporation, the National
Institutes of Health, and the Howard Hughes Medical Institute. Operation
of the ALS is supported by the U.S. Department of Energy, Office
of Basic Energy Sciences.
Publication about this research: D.T. Lodowski, J.A. Pitcher, W.D.
Capel, R.J. Lefkowitz, J.J.G. Tesmer, "Keeping G proteins at
bay: A complex between G protein-coupled receptor kinase 2 and Gβγ,"
Science 300, 1256 (2003). |