Biology Reference
In-Depth Information
3 Fine Tuning of PDE4 Gating by Accessory Proteins
In addition to the A
K
inase
A
nchoring
P
roteins (AKAPs) which provide a scaffold
for organizing PDE4 within the cell, other accessory proteins regulate PDE4
activity by interacting with PDE4 regulatory domains (Houslay et al.
2007
).
Examples of both positive and negative regulators of PDE4 activity have been
described (Table
2
). These types of accessory proteins have been shown by
mutational and biochemical analysis to interact with UCR2 or with the C-terminal
regulatory helix. The ability of accessory proteins to stabilize particular PDE4
conformations may be reflected in the tissue-specific distribution of high-affinity
rolipram binding (Zhao et al.
2003
).
Myomegalin was identified as a PDE4-interacting protein by Verde et al. (
2001
).
Myomegalin has multiple tissue variants and can be best viewed as a scaffolding
protein associated with multiple subcellular organelles including golgi, centro-
somes, and skeletal muscle sarcomeres. Myomegalin interacts with long and short
forms of PDE4D (PDE4D3 and PDE4D1, respectively), but not with a supershort
form (PDE4D2) containing a truncated UCR2 (see Fig.
1
). More importantly,
PDE4D retains enzymatic activity when co-immunoprecipitated with myomegalin,
suggesting that myomegalin interacting with the N-terminus of UCR2 may prevent
UCR2 from gating PDE4 activity by closing across the active site. This would be
predicted to impair high-affinity binding of atypical PDE4 inhibitors interacting
with UCR2 in the closed conformation. As myomegalin is highly expressed in
heart, such an accessory protein interaction with PDE4 may decrease the potential
for cardiotoxicity by atypical PDE4 inhibitors (Lehnart et al.
2005
).
Correspondingly, accessory proteins have been described, which likely recog-
nize UCR2 in the closed conformation, thereby increasing sensitivity to atypical
PDE4 inhibitors, such as rolipram (Bolger et al.
2003b
). PDE4A5 was identified
as a potential interactor with the immunophilin AIP/XAP2/ARA9 in a yeast two-
hybrid screen (Bolger et al.
2003a
). The arylhydrocarbon interacting protein
(AIP) interacts with the aryl hydrocarbon receptor, which is needed for transcrip-
tional responses to xenobiotics and for normal cardiac development (Houslay
et al.
2007
). AIP binding to UCR2 inhibits PDE4A5 hydrolysis of cAMP
50%
in a noncompetitive fashion and increases the potency of inhibition by rolipram.
In our model, rolipram may stabilize the protein interaction surface for AIP
binding by shifting the equilibrium of PDE4 from an open to a closed conforma-
tion of UCR2. Accessory proteins binding the LR2 linker region between UCR2
and the catalytic domain, as shown for the SH3 domains of SRC family tyrosyl
kinases in binding to the proline- and arginine-rich LR2 that is unique to PDE4A
(McPhee et al.
1999
), also markedly potentiate rolipram binding and elicit
kinetics of partial competitive inhibition, which would be explained by our
model (Burgin et al.
2010
) if this interaction acted in stabilizing the closed
conformation of UCR2.
DISC1 (disrupted in schizophrenia) also may hold UCR2 in a closed form,
thereby inhibiting the PDE catalytic activity of the complex. Disruption of DISC1
>
