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J. Biol. Chem., Vol. 276, Issue 35, 32407-32410, August 31, 2001
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From the Department of Chemistry, University of Illinois, Chicago, Illinois 60607-7061
Many peripheral proteins involved in cell
signaling translocate to different cell membranes in response to
specific cell stimuli. Because cellular functions and regulation of
these proteins depend on their specific subcellular localization (1),
understanding the mechanisms of membrane targeting is of great
importance. The membrane targeting of diverse peripheral proteins is
mediated by a limited number of membrane-targeting domains, including
protein kinase C (PKC)1
conserved 1 (C1), PKC conserved
2 (C2), and pleckstrin homology domains. Recent structural
and functional studies of individual membrane targeting domains as well
as the peripheral proteins harboring these domains have provided new
insights into the molecular mechanisms underlying the specific
subcellular targeting and activation of peripheral proteins. This
review summarizes the recent progress in our understanding of the
mechanisms of C1 and C2 domain-mediated membrane targeting, with an
emphasis on the correlation between the membrane binding properties of
the C1 and C2 domains and the peripheral proteins containing these
domains and their subcellular targeting behaviors. There are
several excellent reviews (2-6) that contain more exhaustive surveys
on the membrane targeting domains.
The membrane binding of peripheral proteins involves different
types of interactions (Fig. 1) that
depend upon the physicochemical properties of both membrane and
protein. Membranes of different cellular compartments have different
compositions of bulk lipids that can modulate membrane targeting of
proteins either by providing unique microenvironments or by producing
specific lipid metabolites, such as diacylglycerol (DAG) and
phosphoinositides, that function as second messengers. Extensive
structural and mutational studies of phospholipases A2
(PLA2) have shown that their membrane binding surfaces are
composed of cationic, aliphatic, and aromatic residues (7). A recent
study by surface plasmon resonance analysis indicated that cationic
residues primarily accelerate the association of protein to anionic
membrane surfaces, whereas aliphatic residues mainly slow the membrane
dissociation by penetrating into the hydrophobic core of the membrane
(8). Aromatic residues, particularly Trp, which has a preference for
the water-lipid interface (9), play a pivotal role in binding to
zwitterionic PC membranes (7, 10) by affecting both membrane
association and dissociation steps (8). A priori, the
physicochemical principles learned from these in vitro
membrane binding studies should allow the prediction of the subcellular
targeting behaviors of peripheral proteins, provided that the
subcellular targeting is driven mainly by membrane-protein
interactions.
The C1 domain (~50 amino acids) is a cysteine-rich compact
structure that contains five short Structural (12) and mutation (14) studies of PKC Conventional and novel PKCs contain two copies of C1 domains.
Earlier studies on conventional PKC reported the one-to-one stoichiometry of PKC-DAG (25) and PKC-phorbol ester binding (26, 27),
suggesting that only one C1 domain is directly involved in DAG/phorbol
ester binding and PKC activation. A recent study of isolated C1A and
C1B domains of PKCs revealed that C1B domains have much higher
affinities for phorbol 12,13-dibutyrate than C1A domains (28). The only
exception was PKC The subcellular targeting of isolated C1 domains and PKC
holoenzymes in response to DAG and phorbol esters has been measured in
various mammalian cells transfected with green fluorescent protein
(GFP)-tagged proteins (20, 33-39). PKC The C2 domain (~130 residues) was first discovered as the
Ca2+-binding site in conventional PKCs (15). A great number
of proteins containing the C2 domain have been identified since, and
most of them are involved in signal transduction (e.g., PKC,
cytosolic PLA2 (cPLA2), phospholipases C, plant
phospholipase D, and phosphatidylinositol 3-kinase) or membrane
trafficking (e.g., synaptotagmins, rabphilin-3A, and
Unc-13) (2, 3). Structural analyses of multiple C2 domains have
indicated that all C2 domains share a common fold of eight-stranded antiparallel The Ca2+-binding sites of C2 domains are composed of
three variable loops that contain ligands for multiple Ca2+
ions. Structural (43-47) and binding analyses (51-53) have determined the calcium binding stoichiometry, geometry, and affinity for several
C2 domains. Two major roles of Ca2+ ions in the membrane
targeting of the C2 domain have been experimentally demonstrated. The
first role of Ca2+ ions is to provide a bridge between the
C2 domain and anionic phospholipids. This Ca2+ bridge model
is supported by an x-ray structure of the
PKC Non-Ca2+-coordinating protein residues in the
Ca2+-binding loops also play important roles in the
membrane binding and phospholipid selectivity of the C2 domain. A large
degree of structural variations have been found in the
Ca2+-binding loops of C2 domains in terms of both primary
and tertiary structures (43-47). Mutational (56, 57) and labeling (58, 59) studies have identified the residues in the
Ca2+-binding loops that play a key role in membrane
binding. In general, cationic residues on the surface of
Ca2+-binding loops are important for anionic
lipid-selective C2 domains (57, 60), whereas aliphatic and aromatic
residues are essential for PC-selective cPLA2-C2 (56, 58,
59). A predominant cationic cluster in the The subcellular targeting of GFP-tagged C2 domains and
C2-containing peripheral proteins, most notably conventional PKCs and cPLA2, has been studied in different mammalian cells. In
general, the subcellular localization behaviors of C2 domains are
consistent with their in vitro membrane binding properties.
For instance, C2 domains of conventional PKCs that prefer anionic
phospholipids rapidly translocate to plasma membrane (20) and
PC-selective cPLA2-C2 to the perinuclear region in response
to Ca2+ import (65, 66). Also this subcellular localization
pattern of isolated C2 domains correlates with that of peripheral
proteins harboring the C2 domains: i.e. conventional PKCs
translocate to the plasma membrane (33-35, 39) whereas
cPLA2 moves to the perinuclear region (67). Furthermore,
chimera proteins of PKC Some Ca2+-dependent membrane-binding
proteins, including the amino-terminal The majority of peripheral proteins have two (or more) membrane
targeting domains although the presence of extra domains is not
absolutely required for their membrane translocation. This suggests
that their membrane targeting and activation might involve a
synergistic and/or regulatory interplay of the membrane targeting domains. A synergistic action of C1 and C2 domains in the prolonged membrane localization of PKC was demonstrated for PKC In both protein-protein and membrane-protein interactions, the
initial formation of nonspecific collisional complexes, driven by
diffusion and electrostatic forces, is followed by the formation of
tightly bound complexes, which are stabilized by specific interactions (8, 73). The former interactions mainly enhance the association rate
whereas the latter interactions primarily decrease the dissociation rate. For C1 domains, the initial binding is driven by nonspecific electrostatic interactions between cationic residues with bulk anionic
lipids, but the tight complex formation is achieved by both hydrophobic
interactions between hydrophobic C1 residues and the membrane core and
hydrogen bonds between polar C1 residues and DAG (Fig. 2). Accordingly,
the subcellular localization of the C1 domain is determined primarily
by the location of DAG and phorbol ester, although the bulk lipid
composition of the targeting membrane can affect the kinetics of
translocation (20). For anionic lipid-selective C2 domains, the initial
binding is driven by electrostatic interactions via C2-bound
Ca2+, cationic residues, or a combination of both. However,
the paucity of multiple specific interactions required for tight
complex formation renders the binding relatively weak and transient
(20). On the other hand, the membrane binding of PC-selective
cPLA2-C2 is slowly driven by interactions between aromatic
residues and PC molecules (8), but the binding is tight due to membrane
penetration and the resulting hydrophobic interactions. In accordance
with these membrane binding properties, cPLA2-C2 alone can
achieve the membrane localization of cPLA2 in the cell,
whereas both C1 and C2 domains are required for the prolonged membrane
localization of conventional PKC (20, 41). Unlike the case of the C1
domain, the bulk lipid composition of the membrane is an important
determinant of Ca2+-dependent localization of
the C2 domains. For the reliable prediction of subcellular localization
of C2 domains based on their lipid selectivity, the lipid compositions
of various cellular membranes of different cells need to be fully characterized.
Results summarized in this review show that much of the
spatiotemporal dynamics of the peripheral proteins harboring
membrane-binding C1 and C2 domains can be accounted for by the
physicochemical principles that govern their in vitro
membrane binding properties. The subcellular targeting of peripheral
proteins containing a single targeting domain (e.g.
cPLA2) usually reflects the membrane binding properties of
the domain, whereas that of peripheral proteins with multiple C1 and C2
domains is determined by the delicate interplay of the domains and the
synergistic actions of their agonists (e.g. Ca2+
and DAG). The principles learned from these studies should help in
understanding the subcellular targeting of peripheral proteins containing other membrane targeting domains. Because C1 and C2 domains
can also interact with other proteins (42), the subcellular targeting
of some C1- and C2-containing proteins might involve both
membrane-protein and protein-protein interactions. Moreover, protein
phosphorylation might play an important regulatory role in the
subcellular targeting of peripheral proteins (40, 41). Further
systematic studies are required to comprehensively address these
important issues. Finally, cellular translocation studies of peripheral
proteins have been focused mainly on membrane translocation so far. To
fully understand spatiotemporal dynamics and regulation of signaling
peripheral proteins, however, it is necessary to simultaneously monitor
the spatiotemporal dynamics and activities of peripheral proteins as
well as the spatiotemporal dynamics of their stimuli in living cells.
Recent technological advances in light microscopy and cell biology
should greatly facilitate this challenging endeavor.
INTRODUCTION
Membrane-Protein Interactions
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Fig. 1.
Different types of membrane-protein
interactions. Interactions of peripheral proteins with bulk
lipids include coulombic interactions between cationic residues and
anionic lipids (red) (a), interactions between
aromatic residues (green) and zwitterionic lipid
(blue) (b), and hydrophobic interactions
involving aliphatic residues (and Phe) that are, in general, exposed by
conformational changes of protein (c). d,
peripheral proteins can also interact with a lipid second messenger
(magenta) such as DAG.
Structure, Function, and Occurrence of C1 Domains
strands, a short 
-helix, and
two zinc ions (Fig. 2) (11, 12). The C1
domain was first identified as the interaction site for DAG and phorbol
ester in PKCs (13). In conventional (, I,
II, and 
) and novel (
, 
, 
, and 
) PKCs,
the C1 domain occurs in a tandem repeat (C1A and C1B). C1 domains have
been subsequently found in other proteins with diverse functions,
including protein kinase D (PKD/PKCµ), chimaerin, Ras-GRP, Unc-13,
Munc13 isoforms, DAG kinases, and Raf (4). In general, C1 domains show
a high degree of amino acid sequence homology. Some C1 domains,
including those found in atypical PKCs (
and 
/
), however, do
not bind lipids due to minor sequence variations and might be involved
in protein-protein interactions (4). This review will focus mainly on
the C1 domains involved in DAG and phorbol ester binding.
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Fig. 2.
Models of membrane interactions of C1 and C2
domains. PKC -C1B (yellow), PKC-C2
(aqua), and cPLA2-C2 (yellow) are
shown in ribbon diagrams. Also shown are phorbol ester
(white), Zn2+ ions (purple), and
Ca2+ ions (magenta) bound to the domains.
Cationic (blue) and hydrophobic (red) residues
involved in membrane interactions are shown in space-filling
representation. See the text for a detailed description of the
models.
Membrane Binding of C1 Domains
-C1B have
defined the phorbol ester/DAG binding pocket. The polar binding pocket
is located at the tip of the molecule and is surrounded by aliphatic
and aromatic residues, which are adjoined by a ring of cationic
residues in the middle part of the molecule (Fig. 2). A NMR study of
PKC-C1B (15) and a monolayer penetration study of PKC (16) showed
that the hydrophobic residues of the C1 domain penetrate the
membrane for DAG/phorbol ester binding. The phorbol ester binding seals
the polar surface in the binding pocket and thereby generates a
contiguous hydrophobic surface (12), which in turn greatly enhances the
stability of the C1-membrane complex (17, 18). Further mutational
studies of PKC showed that clustered cationic residues in the C1A
domain are involved in nonspecific electrostatic interactions with
anionic phospholipids (19). In agreement with this finding, the
isolated C1 domain repeat (i.e. C1A + C1B) of PKC
exhibits little head group specificity among anionic phospholipids
while discriminating against PC (16). Together these studies on PKC C1
domains have led to a model for C1 domain-membrane interactions
illustrated in Fig. 2. In this model, cationic residues accelerate the
initial adsorption of the C1 domain to the anionic membrane surfaces
and properly position the C1 domain at the membrane surface. Then, the
hydrophobic tip of the domain penetrates the membrane to bind
DAG that is partially buried in the membrane because of its hydrophobic
nature. Because C1 domains with the exposed hydrophobic patch are
subject to protein aggregation in solution, a tightly controlled
triggering mechanism would be necessary for the C1 domain-mediated
membrane targeting. In the case of conventional PKCs, it has been shown
that C1 domains are buried at the resting state and become accessible
to DAG or phorbol esters only after
Ca2+-dependent membrane binding (19, 20). The
C1 domains of PKD/PKCµ (21, 22), Ras-GRP (23), and
2-chimaerin (24) have also been shown to drive the
cellular membrane targeting of the corresponding peripheral proteins in
response to DAG and phorbol esters. Because no detailed analysis of
their interactions with membranes has been reported, it is not known
whether the mechanisms of C1 domain-mediated membrane binding of these
peripheral proteins are similar to that of PKCs.
Differential Roles of Multiple C1 Domains in PKC
, the C1A and C1B domains of which show comparably
high affinities. For PKC, good correlation was observed between the
intrinsic phorbol ester affinities of C1A and C1B domains and their
relative importance in phorbol ester-induced activation (29),
supporting the notion that the disparate roles of C1 domains mainly
derive from their different intrinsic affinities for phorbol esters.
More recently, however, it was shown that C1A and C1B domains of PKC
play an equivalent role in cellular membrane translocation in response
to phorbol 12-myristate 13-acetate (PMA) despite their distinct phorbol
ester affinities (30). To date, correlation between the intrinsic DAG
affinities of C1 domains and their relative importance in DAG-dependent PKC activation has not been documented. A
series of spectroscopic vesicle binding studies of PKC indicated
that PKC contains two phorbol ester binding sites with high and low affinities and that DAG and phorbol esters bind to the two sites with
opposite affinity (31, 32). The notion that DAG and phorbol esters
might have different C1A versus C1B selectivity was further supported by the finding that the C1A domain is exclusively involved in
the DAG-induced vesicle binding and activation of PKC (16). Clearly, more studies are needed to fully understand these complex interactions of the C1 domains of PKC with their ligands.
Subcellular Targeting by C1 Domains
translocated to plasma
membrane in response to PMA in COS-7 cells (33). In RBL cells,
PKC and its C1A, C1B, and C1A-C1B domains all showed the
translocation to plasma membrane in response to PMA or DAG (35). As is
the case with PKC, PKCII (40, 41), PKC (34), PKC (39), and PKC-C1A-C1B (38) were shown to translocate to
plasma membrane in response to PMA or DAG. In the case of PKC holoenzymes, Ca2+ enhanced the rate of translocation of
proteins but did not affect their localization. Later studies showed
that whereas PMA and other hydrophobic phorbol esters induced the
initial translocation of PKC to the plasma membrane, less
hydrophobic DAG and PDB caused PKC to translocate to the perinuclear
region (36, 37). Our cell study2
of GFP-PKC with a fluorescent phorbol ester analog, sapintoxin D,
supported the notion that the differential subcellular localization of
C1 ligands is a main determinant of the differential subcellular targeting of PKCs. This in turn suggests that the in vitro
membrane binding and the subcellular targeting of C1 domain are driven by the same forces. Binding to neither adapter proteins nor
cytoskeleton appears to contribute significantly to the subcellular
targeting of PKC-C1 domains because the putative adapter binding site
is not located in the C1 domains (42) and the cytoskeleton inhibitors show little effect on C1 domain translocation (35, 39).
Structure, Function, and Occurrence of C2 Domains
-sandwich connected by variable loops, with the Ca2+-binding sites located at one side of the domain (Fig.
2) (43-47). When compared with C1 domains, C2 domains show a larger
degree of variation in amino acid sequence, particularly in the loop regions (2, 3). Consistent with this finding, C2 domains show greater
functional diversities. Most Ca2+-dependent
membrane-binding C2 domains prefer anionic membranes to zwitterionic
ones; however, cPLA2-C2 strongly favors PC membranes (48).
Among anionic lipid-selective C2 domains, PKC-C2 (16) and
PLC1-C2 (49) exhibit PS selectivity. Furthermore, there are many non-Ca2+-binding C2 domains; some of them, such as
PTEN-C2 (50), still bind the membrane, and others might be involved in
protein-protein interactions (2, 3). This review will mainly deal with
the C2 domains that bind phospholipids in a
Ca2+-dependent manner.
Ca2+-dependent Membrane Binding of
C2 Domains
-C2-(Ca2+)2-PS complex (46), showing that
a short-chain PS molecule is specifically coordinated to a
Ca2+ ion and other residues in the Ca2+-binding
loops. This structure also accounts for the PS selectivity of PKC-C2
(16). The second role of Ca2+ ions is to induce intra- or
interdomain conformational changes, which in turn trigger
membrane-protein interactions. Despite earlier negative reports (43),
accumulating evidence has supported the occurrence of
Ca2+-induced conformational changes in the C2 domain (44,
52-55). Recent structure-function studies of the C2 domains of PKC
(18) and cPLA2 (56), both of which bind two
Ca2+ ions, showed that two Ca2+ ions play
distinct roles, with one primarily involved in inducing the
conformational changes and the other in Ca2+ bridging. The
main difference is that Ca2+-induced conformational changes
are critical for the membrane binding of cPLA2-C2, whereas
Ca2+ bridging is a relatively more important role of
PKC-C2.
-sandwich region has been
implicated in inositol polyphosphate binding of synaptotagmin II
(61) but does not significantly affect the membrane binding of
conventional PKCs (62) and cPLA2 (56). Together, these
in vitro studies have indicated that anionic lipid-selective
C2 domains and cPLA2-C2 have distinct membrane binding
modes. As shown in Fig. 2, PKC-C2 binds to the membrane in an
orientation that optimizes its electrostatic interactions with the
anionic membrane (46, 57, 60), whereas cPLA2-C2 binds to
the membrane in an orientation that optimizes the membrane penetration
of its hydrophobic residues (56, 58, 59, 63). Interestingly, membrane
binding properties of cPLA2 and its C2 domain are similar
(56, 64), whereas those of PKC and its C2 domain have noticeable
differences (16, 18). This discrepancy implies that the relative
contribution of a C2 domain to the membrane binding of a peripheral
protein depends on the structural context of the protein, particularly
on the presence of other membrane targeting domains in the same molecule.
Subcellular Targeting by C2 Domains
and cPLA2 containing the C2
domains of cPLA2 and PKC, respectively, are localized to
the perinuclear region and plasma membrane,
respectively.3 Thus, it is
expected that anionic lipid-selective C2 domains (and C2-bearing
proteins) will translocate to plasma membrane and that PC-selective C2
domains (and C2-bearing proteins) will translocate to the perinuclear
region. When conventional PKCs are activated by both C1 ligand and
Ca2+ ionophore, however, their subcellular localization is
governed primarily by the subcellular location of C1 ligands although
the C2 domain also contributes to the kinetics and energetics of
translocation (20). Our recent study3 of PKC-C2,
cPLA2-C2, and their mutants demonstrated quantitative correlation between the subcellular targeting and in vitro
membrane binding: i.e. PKC-C2 rapidly but transiently
translocates to plasma membrane, but cPLA2-C2 slowly but
irreversibly translocates to the perinuclear region in response to
Ca2+ import. Also subcellular translocation kinetics of
mutants exhibited good correlation with their altered in
vitro membrane binding kinetics. Thus, it appears that the
subcellular targeting of these C2 domains is primarily driven by forces
that govern their membrane binding.
Membrane Targeting by C2-like Domains
-barrel domain of
5-lipoxygenase (68) and the domain III of calpains (69, 70), have C2
domain-like structures. In particular, the C2-like domain of
5-lipoxygenase has been shown to have specific Ca2+ ligands
(68) and to be responsible for the
Ca2+-dependent nuclear translocation of
5-lipoxygenase (71). The C2-like domain of 5-lipoxygenase has been
shown to have PC selectiv-ity because of the presence of aromatic
residues in the putative Ca2+-binding
loops.4
Interactions of C1 and C2 Domains
(20) and
PKCII (41). The regulatory interactions between C1 and C2 domains have also been suggested for the targeting and regulation of
different PKC isoforms. In the case of PKC, a single anionic residue
in the C1A domain is implicated in the tethering of C1A to the other
part of the molecule, most likely the C2 domain (19). The putative
tethering keeps the protein in an inactive conformation at the resting
state and is disrupted specifically by the
Ca2+-dependent binding of the C2 domain to PS
in the membrane, which in turn leads to the membrane penetration and
DAG binding of the C1A domain and PKC activation. Similarly, it was
suggested that the C2-like domain of novel PKC interacts with the C1
domain to regulate the enzyme activity (72). Further studies will
reveal more examples of interdomain interactions in the membrane
targeting of peripheral domains.
Roles of Bulk Lipids and Lipid Second Messengers
Conclusions and Future Direction
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ACKNOWLEDGEMENTS |
|---|
I thank M. Medkova, L. Bittova, R. Stahelin, J. Rafter, S. Das, M. Sumandea, S. Kulkarni, M. Digman, and B. Ananayarayanan for their contributions. I apologize to the many authors whose work could not be cited directly because of page limitation.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This is the fourth article of four in the "Membrane Protein Structural Biology Minireview Series." This work was supported by National Institutes of Health Grants GM52598 and GM53987.
Established Investigator of the American Heart Association. To
whom correspondence should be addressed: Dept. of Chemistry (M/C 111),
University of Illinois, 845 West Taylor St., Chicago, IL 60607-7061.
Tel.: 312-996-4883; Fax: 312-996-2183; E-mail: wcho@uic.edu.
Published, JBC Papers in Press, June 29, 2001, DOI 10.1074/jbc.R100007200
2 J. Rafter and W. Cho, manuscript in preparation.
3 R. Stahelin, J. Rafter, and W. Cho, manuscript in preparation.
4 S. Kulkarni and W. Cho, manuscript in preparation.
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ABBREVIATIONS |
|---|
The abbreviations used are: PKC, protein kinase C; PLA2, phospholipase A2; cPLA2, cytosolic phospholipase A2; GRP, gastrin-releasing peptide fragment; GFP, green fluorescent protein; DAG, diacylglycerol; PC, phosphatidylcholine; PS, phosphatidylserine; PMA, phorbol 12-myristate 13-acetate.
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INTRODUCTION
Membrane-Protein Interactions