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From the Prenylation is a type of lipid modification involving covalent
addition of either farnesyl (15-carbon) or more commonly geranylgeranyl
(20-carbon) isoprenoids via thioether linkages to cysteine residues at
or near the C terminus of intracellular proteins. The attached lipid is
required for proper function of the modified protein, either as a
mediator of membrane association or a determinant for specific
protein-protein interactions. Prenylated proteins play crucial roles in
such vital cellular processes as signal transduction and intracellular
trafficking pathways. This review focuses primarily on the enzymology
of protein prenylation; the reader is directed to several other reviews
for a more detailed description of related aspects not covered
here(1, 2, 3, 4, 5, 6, 7) . The enzymes responsible for isoprenoid addition to proteins have
been identified and characterized at a molecular level both in
mammalian systems and in lower eukaryotes. Three distinct protein
prenyltransferases can be classified in two functional classes: the
CAAX prenyltransferases, identified by their lipid substrate
and termed protein farnesyltransferase (FTase) (
CAAX Prenyltransferases, Farnesyltransferase and
Geranylgeranyltransferase Type I The first protein prenyltransferase identified was protein
FTase (9) . The enzyme is a heterodimer consisting of 48-kDa
( One important
property of both FTase and GGTase-I is that they can recognize short
peptides containing appropriate CAAX motifs as
substrates(1, 3) . Specificity in recognition of
CA The genes encoding both FTase and GGTase-I have been cloned from a
number of mammalian and fungal species(2, 3) . The
FTase and GGTase-I are zinc
metalloenzymes, and each contains a single zinc atom required for
activity(11, 20, 21, 22) . It is
likely that the role of zinc is the same in both enzymes. The zinc atom
is not required for isoprenoid substrate binding but is required for
protein and peptide substrate binding by both FTase (20) and
GGTase-I. ( FTase and GGTase-I can bind
either substrate independently(12, 25) . Binding of
peptide substrate to FTase has been examined by NMR, revealing that the
CAAX sequence of a peptide substrate adopts a Type I
Steady-state kinetic data on both enzymes initially indicated that
their reactions proceed via a random sequential mechanism, an
interpretation also consistent with the substrate binding studies (22, 25, 30) . However, isotope partitioning
studies have indicated that the preferred catalytic pathway is through
the enzyme-isoprenoid binary complex, while the pathway through the
enzyme-peptide binary complex is much slower(24, 31) .
A more detailed kinetic study that included presteady-state analysis
confirmed that, at least in the case of FTase, the random sequential
mechanism is only an approximate description of a true ordered
sequential path(32) . Additionally, these studies established
that FTase binds FPP in a two-step process to form FTase
Figure 1:
Kinetic mechanism of protein
farnesyltransferase. The overall kinetic pathway for the FTase reaction
is shown. Data are primarily derived from (32) but are also
consistent with studies reported in Refs. 25, 30, and 31. E,
FTase; E*, the form of FTase that binds FPP with high
affinity; pep
The precise chemical
mechanism of the reactions catalyzed by FTase and GGTase-I is still
undefined. A recent study using fluoro-substituted FPP analogs has been
interpreted to indicate that the mechanism is electrophilic in
nature(33) , whereas analysis of the stereochemical course of
the reaction using FPP with chiral deuterium-for-hydrogen substitutions
at the C-1 carbon indicated that the reaction proceeds with inversion,
suggesting a more nucleophilic mechanism. ( Structure-function analyses of FTase and GGTase-I are beginning to
provide some information on these enzymes. The CAAX prenyltransferases are generally quite
selective for their respective protein substrates. However,
cross-specificity has been
observed(13, 36, 37) , and such capacity to
modify alternate substrates may be of biological significance. In this
regard, yeast lacking RAM1 exhibit growth defects that can be partially
suppressed by overexpression of CDC43 (the
Farnesyltransferase Inhibitor Studies Development of protein prenylation inhibitors is an active
area of research. The primary driving force for such efforts came from
the finding that oncogenic forms of Ras proteins require farnesylation
for their ability to transform cells. Inhibitors of FTase that have
been synthesized or identified include analogs of both
substrates(41, 42, 43, 44) , fused
forms of the two substrates(45) , and a number of natural
products and other compounds identified in screening
programs(46, 47) . Many of these inhibitors block Ras
processing and inhibit the growth of Ras-transformed
cells(41) . The potential for use of FTase inhibitors in cancer
chemotherapy is highlighted by a recent study in which administration
of an FTase inhibitor to mice bearing tumors resulting from expression
of an oncogenic Ha-Ras transgene led to almost complete tumor
regression without visible toxicity to the animal(48) . An
open question in this field is why FTase inhibitors exhibit such low
toxicity even though they can apparently completely block processing of
Ras and other crucial farnesylated proteins in cells. Furthermore, the
presence of oncogenic Ras in cancer cells is not an absolute predictor
of whether the cells will respond to FTase inhibitors. Many types of
cancer cells not containing oncogenic forms of Ras respond to
inhibitors, and non-responsive cells that nonetheless contain activated
Ras alleles have been identified(49, 50) .
Possibilities to explain the current data include: (a) certain
forms of Ras such as K-RasB may be resistant to FTase
inhibitors(36, 51) , a critical issue since K-RasB is
the form of Ras most commonly found mutated in human
cancers(52) ; (b) the aforementioned potential for
GGTase-I to modify FTase substrates(36) ; and (c) the
finding that farnesylated proteins other than Ras may be important in
maintaining the transformed phenotype of cancer cells, and activities
of these proteins are more critically dependent on maintenance of FTase
activity (53) .
Prenylation of Rab Proteins, Rab
Geranylgeranyltransferase or Protein Geranylgeranyltransferase Type-II A family of Ras-related GTP-binding proteins designated Rab
in mammals and Ypt/Sec4 in yeast requires modification by
geranylgeranyl isoprenoids for their action as molecular switches
regulating vesicular transport in exocytic and endocytic
pathways(54, 55) . However, the majority of Rab
proteins do not contain a CAAX sequence at the C terminus but
rather contain a so-called CC or CXC prenylation
motif(6) . An enzymatic activity that catalyzes geranylgeranyl
addition to Rabs was purified from rat brain and shown to consist of
two chromatographically separable components, initially designated
components A and B(8, 56) . Structural and functional
data described below led to the assignment of component B as the
catalytic component, now referred to as Rab geranylgeranyltransferase
or protein geranylgeranyltransferase type-II (GGTase-II), and component
A as a Rab escort protein (REP). GGTase-II from rat brain is a
heterodimeric enzyme composed of a 60-kDa GGTase-II has a strict lipid and
protein substrate specificity. GGTase-II binds GGPP with submicromolar
affinity to form a stable complex and does not recognize FPP or
geranyldiphosphate. ( Both cysteine residues at the
C terminus of Rabs are modified by geranylgeranyl groups(64) .
Recent studies with mutant Rab1A substrates that could only accept one
prenyl group suggest that there is not a strict order of addition of
the isoprenoid to the acceptor residues in either the Cys-Cys- or
Cys-X-Cys-containing substrates but that the N-terminal
cysteine is somewhat preferred(61) . Additionally, the stable
monoprenyl-Rab The
Prenylation of Rab Proteins, Rab Escort Proteins In order to undergo prenylation, newly synthesized Rabs must
bind and form a stable complex with REP, which is then recognized by
GGTase-II(60) . After prenylation, the modified Rab remains
associated with REP, presumably because it is too hydrophobic to be
released into aqueous solution. The REP The REP-Rab
interaction may be mediated by multiple binding sites in Rab proteins,
one involving the C-terminal region and the other one or more regions
of upstream Rab sequences. Rab3A has a lower V Two REPs that share 75% identity have been identified in mammalian
cells(58) . REP-1 is the product of the choroideremia (CHM)
gene on the X chromosome, and REP-2 (or CHM-like) is encoded by an
intronless gene on chromosome 1(58, 70) . CHM is a
retinal degeneration disease, classified under the broad group of
retinitis pigmentosa, characterized by slowly progressive peripheral
retinal degeneration leading to complete degeneration and blindness by
middle age(71) . CHM is caused by deletions in
REP-1(72) . The fact that patients with deletions in the
ubiquitously expressed CHM gene have no other clinical abnormality
other than the retinal lesion and that CHM lymphoblasts retain Rab
prenylation activity suggested that REP-1 function could be partially
compensated by REP-2. In agreement with this hypothesis, REP-2 is as
effective as REP-1 in assisting in the geranylgeranylation of most Rabs (58) . However, one Rab protein, Ram/Rab27, was found
selectively unprenylated in CHM lymphoblasts, suggesting that REP-2
cannot assist effectively in its prenylation(73) . These
results raise the possibility that the selective dysfunction of Rab27
may lead to retinal degeneration in CHM. A gene encoding the yeast
homologue of REP has been identified as MSI4/MRS6(74, 75) . MSI4/MRS6 is an essential gene required for
geranylgeranylation of yeast Rabs, suggesting that there is only one
REP in yeast. Loss of the MSI4/MRS6-encoded protein
leads to defects in prenylation and membrane association of both Ypt1
and Sec4(75, 76) . There has been major progress on the enzymology of protein
prenylation since the isolation of the first enzyme in 1990. Efforts to
design selective cell-active inhibitors of FTase in particular have
been quite successful and have been greatly aided by the acquisition of
mechanistic information on the enzymes. There still is much to be
learned about these enzymes, however, including the question of whether
additional enzymes exist(77) , and it is likely that many of
these secrets will yield to the enzymologist and structural biologist
in the next 5 years. The ever increasing evidence that inhibitors of
protein prenylation could be effective therapeutic agents in the
treatment of many human cancers will continue to drive much of these
efforts. Beyond the enzymology, the challenge is to understand the role
of prenyl groups in mediating the function of the modified proteins, in
particular to unravel the mechanism by which prenyl groups mediate
protein-membrane and protein-protein interactions(78) . Another
important implication resulting from the research in this field was the
identification of a prenylation defect as the molecular defect in one
human hereditary disease, choroideremia. Understanding the role of
REP-1 in the geranylgeranylation of Rab proteins and the pathogenesis
of CHM will contribute to a better understanding of the role of
prenylated Rab GTPases in vital cellular processes as well as the
development of rational therapies for the disease.
Volume 271,
Number 10,
Issue of March 8, 1996 pp. 5289-5292
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
INTRODUCTION
CAAX Prenyltransferases, Farnesyltransferase and
Geranylgeranyltransferase Type I
Farnesyltransferase Inhibitor Studies
Prenylation of Rab Proteins, Rab
Geranylgeranyltransferase or Protein Geranylgeranyltransferase Type-II
Prenylation of Rab Proteins, Rab Escort Proteins
Concluding Remarks
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
)and protein
geranylgeranyltransferase type I (GGTase-I); and the Rab
geranylgeranyltransferase or protein geranylgeranyltransferase type II
(GGTase-II) (Table 1). FTase and GGTase-I are designated CAAX prenyltransferases since they act on proteins containing an
invariant cysteine residue fourth from the C terminus in the context of
a prenylation motif commonly referred to as the ``CAAX box''(1, 3) . Substrates for FTase include
Ras GTPases, lamin B, several proteins involved in visual signal
transduction, and fungal mating
factors(1, 2, 5) . Known targets of GGTase-I
include most subunits of heterotrimeric G proteins and
Ras-related GTPases such as members of the Ras and Rac/Rho
families(1, 6) . GGTase-II attaches geranylgeranyl
groups to two C-terminal cysteines in Ras-related GTPases of a single
family, the Rab family (Ypt/Sec4 in lower eukaryotes) that terminates
in Cys-Cys or Cys-X-Cys motifs(6, 8) .
) and 46-kDa (
) subunit
polypeptides(9) ; the nomenclature is
chosen since the
subunit is also a component of GGTase-I (see
below). Subsequent characterization of GGTase-I showed it too consists
of two subunits, the 48-kDa subunit shared with FTase, i.e. and a 43-kDa polypeptide
(
) (10, 11, 12) .
Characterization of the substrate specificities of the FTase and
GGTase-I confirmed the importance of the CAAX motif of the
protein substrates for enzyme
recognition(9, 11, 12, 13) . Both
enzymes require that protein substrates contain a Cys residue fourth
from the C terminus, while the C-terminal residue (i.e. the X of the CAAX motif) in general determines which of
the two enzymes act on the protein. If X is Ser, Met, Ala, or
Gln, the protein is processed by FTase while Leu at this positions
directs modification by GGTase-I(1, 3) , making it
possible to predict with reasonable accuracy the type of prenyl
modification on a protein by its primary sequence.
A
X sequences by
these enzymes indicates that the A position has a
relaxed amino acid specificity, while variability at A and X is more restricted(14) . Moreover,
substitution at the A position by an aromatic
residue in the context of a tetrapeptide creates peptides that are poor
substrates for the enzymes but very potent competitive
inhibitors(15) . One such peptide, CVFM, has served as the
basis for design of peptidomimetic inhibitors of FTase (see below). and
subunits of mammalian FTase
show about 30 and 37% identity with the proteins encoded by the Saccharomyces cerevisiae genes RAM2 and RAM1
(also known as DPR1),
respectively(16, 17, 18) . These two genes
were originally identified in a genetic screen of an
RAS2, a mutationally activated RAS
allele(2, 4) . RAM1 was also identified based on its
involvement in a-factor processing and as a suppressor of G
protein function(4) . cDNA clones encoding
have been isolated from rat and human libraries (19) .
The cDNAs encode polypeptides of 377 residues, which share 30% identity
with a yeast gene known as CDC43/CAL1. The CAL1 gene was isolated based on a
Ca
-dependent phenotype, while CDC43 was
isolated based on a temperature-sensitive defect in cell polarity and
also exhibits defects in localization of budding and
secretion(2, 4) .
)It is not yet known whether the zinc plays a
structural role or whether it is directly involved in catalysis. One
possibility for a catalytic role of the zinc is that the metal could
activate the sulfhydryl of the substrate protein cysteine residue and
make it more nucleophilic. There is evidence for such a mechanism in a
DNA repair enzyme termed Ada, which catalyzes a reaction chemically
similar to that of FTase(23) . Metal substitution studies
combined with spectroscopic analysis could provide evidence for such a
mechanism in the CAAX prenyltransferases. In this regard, the
zinc in GGTase-I can be replaced by Cd with retention
of enzymatic activity(24) , although the
Cd
-substituted enzyme exhibits somewhat altered
specificity for substrates.
Neither Zn nor Mg
alone restores the activity of
metal-depleted FTase, but addition of both Zn
and
Mg
fully restores activity(11, 20) .
The dependence on millimolar levels of Mg
for full
activity indicates that this metal is probably not an integral
component of FTase(11, 20) . Somewhat surprisingly,
the activity of metal-depleted GGTase-I can be restored with
Zn
alone, in contrast to the strict Mg
requirement for FTase activity.
While the mechanistic
significance of this observation is not yet clear, the lack of a
requirement for Mg exhibited by GGTase-I highlights
the importance of determining the precise role(s) for the metal ions in
the function of both these enzymes.
-turn conformation when bound to the enzyme(26) . A
similar study conducted with a peptidomimetic inhibitor of FTase
revealed a slightly different conformation most closely approximating a
Type III -turn(27) . Binding of isoprenoid substrate by
either enzyme is of such high affinity that the complex can be isolated
by gel filtration. No covalent adduct is involved, however, because the
isoprenoid diphosphate can be released intact upon enzyme denaturation (12, 25) . The binding sites for both substrates of
these enzymes are thought to predominately reside on their
subunits. Photoactivatable isoprenoid analogs cross-link to the
subunits of both FTase and GGTase-I(24, 28) . Both
protein and peptide substrates can be cross-linked to
(25, 29) , while divalent
affinity-labeled short peptide substrates are cross-linked to both the
and subunits of FTase upon photoactivation(29) ;
the latter result suggests that the binding site for the peptide
substrate may be near the interface of the two subunits. 
FPP*,
with the second step presumably involving a conformational change in
the enzyme-substrate complex. FTaseFPP* then rapidly reacts with
the peptide substrate to form a product, and product release is the
rate-limiting step in catalysis(32) . A scheme of the reaction
catalyzed by FTase is shown in Fig. 1.
SH, the C-terminal peptide of protein
substrates that contain the appropriate CAAX motif (GLPCVVM in
the studies from which the data were
derived).
)Additional
studies will be required to firmly establish the chemical mechanism. subunits of
GGTase-I and FTase share about 30% identity, with the highest homology
in the central regions(19) . In vitro mutagenesis has
identified a mutation in the yeast subunit (S159N)
based on suppression of the cal1 (GGTase-I null) phenotype. The mutant
enzyme shows an increased ability to farnesylate a GGTase-I substrate
while its ability to modify a standard FTase substrate is
reduced(34) , suggesting that this residue may be in the
peptide substrate binding site. Deletion of 51 residues from the N
terminus of the rat subunit does not affect
enzyme activity, but removal of 106 residues from the N terminus or 5
residues from the C terminus of the subunit abolished FTase activity
when co-expressed with
(35) . Mutation of
Lys-164 to Asn in produced a polypeptide that
still dimerized with
, and the resulting FTase
produced retains its ability to bind substrates, but the mutant enzyme
had no activity(35) . These data are probably the best evidence
to date that the subunit has a direct role in the catalysis by
FTase. subunit), suggesting that GGTase-I can at least partially modify
substrates of FTase(38) . CDC43 null mutants are not viable,
but overexpression of two essential substrates of this enzyme, Rho1 and
Cdc42, allows growth in a RAM1-dependent manner; presumably FTase
prenylates these substrates of GGTase-I when they are
overproduced(38, 39) . A specific form of mammalian
Ras, K-RasB, can serve as a relatively efficient substrate for both
FTase and GGTase-I(36) ; this dual ability is also seen for a
related protein termed R-Ras2(40) . Additionally, a Ras-related
GTPase implicated in organization of the actin cytoskeleton termed RhoB
can be modified by either farnesyl or geranylgeranyl, and both
isoprenoids can be transferred to the protein by GGTase-I (37) .
subunit
() and a 38-kDa
()
subunit that are homologous to the
and subunits of the
CAAX prenyltransferases(57) . GGTase-II shares many
characteristics with the CAAX prenyltransferases. Association
of both subunits of the heterodimer is required for catalytic
activity(57, 58) . The reaction requires millimolar
levels of Mg, but Rab prenylation is inhibited by
micromolar concentrations of Zn
for reasons that are
at present unclear(8) .
)A striking difference between
GGTase-II and the CAAX prenyltransferases concerns the
recognition of the peptide substrate. Peptides corresponding to
C-terminal amino acids of Rab proteins do not bind to GGTase-II nor
compete for prenylation of full-length Rab3A(8, 59) .
These observations are explained by the finding that the actual
substrate for GGTase-II is a complex of Rab and REP. REP binds newly
synthesized Rab substrates and presents them to GGTase-II so that
prenyl transfer to Rabs occurs(60) . GGTase-II itself does not
stably bind Rabs(61) , and REP is required for even one round
of catalysis. All Rabs tested to date are substrates for
GGTase-II(58, 62) . While no other protein substrates
have been identified, it is possible that a protein kinase in yeast is
processed by this enzyme(63) .REP complex could be isolated, suggesting that each
isoprenoid transfer is an independent reaction(61) . and subunits of GGTase-II in S. cerevisiae have
been identified as the products of the BET4 (previously known
as MAD2) and BET2 genes, respectively, that share 24
and 52% identity with the and subunits of the mammalian
enzyme(65, 66) . Yeast GGTase-II requires the presence
of both BET4 and BET2 gene products for activity, and
mutations in either gene lead to defects in geranylgeranylation and
membrane association of Ypt1 and Sec4(65, 66) . A
mutation termed bet2-1 has been identified that results in an
enzyme with a reduced affinity for GGPP. This mutation can be
suppressed by the overexpression of BTS1, which encodes a GGPP
synthase(67) , suggesting that the subunit
is directly involved in GGPP binding.
Rab complex is then
competent for membrane delivery of prenylated Rabs(68) ,
possibly via a membrane-bound Rab receptor. Free REP is then released
and can support another round of Rab prenylation.
than wild-type Rab1A, and exchanging the last 10 amino acids
between the two proteins reverses their kinetics of
prenylation(58) . This V effect may
reflect differences in binding of the prenylated C terminus to REP,
because V appears to be largely determined by
the stability of the REPRab complex(60) . There is
evidence for additional REP recognition sites on Rab proteins. Rab1A
that contains two Ser-for-Cys substitutions at the C terminus cannot
accept prenyl groups yet still binds to REP and competes for
prenylation of the wild-type protein(56, 61) . Two
putative upstream regions in Rabs have been identified. One corresponds
to the L3/3 region in Ras(62) , and another is an
N-terminal region containing a conserved lysine residue (69) .
))))
We thank the members of our laboratories for
contributions to this work and Kristy Thompson for editorial
assistance. M. C. S. acknowledges Mike Brown and Joe Goldstein for
support and advice.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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