Diacylglycerol Signaling

4 Diacylglycerol Signaling
cPKC (α,β,γ)
nPKC (δ,ε,η,θ)
α1,β1 chimaerin
α2,β2 chimaerin
DGK (β,γ)
PKD (1,2,3)
RasGRP (1,2,3,4)
MRCK (α,β,γ)
Munc13 (1,2ub)
Munc13 (2,3)
Pseudosubstrate
C1 domain
C2 domain
Catalytic domain
SH2 domain
S/T K
Rac GAP
Cdc25
S/T K
DGKc
S/T K
Recoverin homologous (RVH) domain Citron homology domain (CH)
EF-hands
p21-binding domain (PBD)
PH domain
Munc13 homology domain 1 (MHD1)
REM domain
Coiled-coil domain
Munc13 homology domain 2 (MHD2)
Fig. 4.2 C1 domain-containing proteins. The primary structures of C1 domain-containing
proteins. PKC = Protein kinase C, DGK = diacylglycerol kinase, PKD = protein kinase D,
RasGRP = Ras guanine-releasing protein, MRCK = myotonic dystrophy kinase-related Cdc42binding
kinase, Munc13 = mammalian unc13, S/T K = Ser/Thr kinase, Rac GAP = Rac GTPaseactivating
protein, DGKc = DGK catalytic region, Cdc25 = Cdc25 homology domain
the target proteins of the appropriate DAG pool among the numerous reservoirs
of this lipid in the cell. These DAG-modulated proteins have distinct catalytic
activities (Fig. 4.2), except the Munc13 family members, which are exclusively
scaffolding proteins.
The principal DAG effect on responsive proteins is considered to be protein
translocation to membranes, mediated by its direct binding to the C1 domain
(Johnson et al. 1998). The latest discoveries have nonetheless broadened this
concept to include modulation of protein activity and localization in specific cell
membrane subdomains as C1-mediated DAG functions (Hall et al. 2005).
The recent description of the b2-chimaerin crystal structure (Canagarajah et al.
2004), the first for a complete C1 domain-containing protein, has helped to clarify
C1 domain function. This study showed that, in the protein inactive conformation,
both the catalytic and the C1 domains are buried. This specific folding is stabilized
by intramolecular interactions that cover C1 domain hydrophobic residues and the
DAG binding groove, yielding a protein unable to sense DAG. According to
these data, b2-chimaerin would require previous signals that would expose the
catalytic and C1 domains and subsequently allow DAG binding. This would
promote closer contact with DAG-enriched membranes, favoring protein activity.
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