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J. Biol. Chem., Vol. 276, Issue 43, 39501-39504, October 26, 2001

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MINIREVIEW
The Biology and Enzymology of Protein N-Myristoylation^*,

Thalia A. Farazi^§, Gabriel Waksman^¶, and Jeffrey I. Gordon

From the Departments of  Molecular Biology and Pharmacology and ^¶ Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110

	INTRODUCTION

TOP INTRODUCTION Myristoyl-CoA:Protein N-... Nmt Is a Therapeutic... Kinetic Studies of S.... Reaction Mechanism of Nmt Prospectus REFERENCES

Protein N-myristoylation refers to the covalent attachment of myristate, a 14-carbon saturated fatty acid, to the N-terminal glycine of eukaryotic and viral proteins. N-Myristoylproteins have diverse functions and intracellular destinations. They include proteins involved in a wide variety of signal transduction cascades. In general, N-myristoylation is an irreversible protein modification that occurs co-translationally following removal of the initiator methionine residue by cellular methionylaminopeptidases (1, 2). N-Myristoylation can also occur post-translationally, as in the case of the pro-apoptotic protein BID where proteolytic cleavage by caspase 8 reveals a "hidden" myristoylation motif (3).

N-Myristoylation promotes weak and reversible protein-membrane and protein-protein interactions (4, 5). Typically, myristate acts in concert with other mechanisms to regulate protein targeting and function. Some proteins (e.g. MARCKS, Src) employ "myristoyl-electrostatic switches" where membrane association is promoted by myristate plus electrostatic interactions between positively charged protein side chains and negatively charged membrane phospholipids (6, 7). In other N-myristoylproteins, ligand binding (Arfs, recoverin (8, 9)) or proteolytic cleavage (HIV-1 Pr55^gag/p17MA (10)) produces a conformational change that exposes or sequesters the acyl chain ("myristoyl-conformational switch").

A subset of proteins undergoes post-translational covalent modification with one or more palmitoyl groups after N-myristoylation. Examples of these dually acylated proteins include members of the Src family of tyrosine kinases (Fyn, Lck),  subunits of heterotrimeric G-proteins, endothelial nitric-oxide synthase, and the yeast vacuolar protein Vac8p (11). Cys serves as the acceptor site for palmitate. S-Palmitoylation is reversible, providing a mechanism for regulated interactions between these N-myristoylproteins and cellular membranes and/or other proteins (7, 12). For example, turnover of the palmitoyl moiety in N-myristoylated G_i subunits is stimulated by activation of the 5-hydroxytryptamine-1a receptor (13). Depalmitoylation of G_i has no overt effects on membrane association (14) but may have functional consequences for G-protein de-activation; in vitro studies have shown that S-acylated G_i is resistant to the GTPase-activating protein activity of RGS (regulators of G-protein signaling) proteins (15).

The "kinetic bilayer trapping" hypothesis (16) was proposed to explain the operation of this "dual fatty acylation switch." According to the hypothesis, proteins with myristate are able to transiently interact with membranes. This allows subsequent palmitoylation by plasma membrane-associated palmitoyl S-transferase (17) and stable membrane association because of a slower off rate of the dually acylated product. Dual acylation also influences compartmentalization to specialized plasmalemmal microdomains (18). In lymphocytes, dual acylation of non-receptor tyrosine kinases (Fyn, Lck) is necessary for their targeting to lipid rafts. Inhibiting S-acylation by Cys to Ser mutation, or 2-bromopalmitate treatment, delocalizes these kinases from rafts and is associated with loss of signaling through the T-cell receptor (19, 20). Mutagenesis studies indicate that both N-myristoylation and S-palmitoylation are needed to target endothelial nitric-oxide synthase to caveolae (21).

	Myristoyl-CoA:Protein N-Myristoyltransferase Is an Essential Enzyme

TOP INTRODUCTION Myristoyl-CoA:Protein N-... Nmt Is a Therapeutic... Kinetic Studies of S.... Reaction Mechanism of Nmt Prospectus REFERENCES

N-Myristoylation is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (Nmt),¹ a member of the GNAT superfamily of proteins (22). Nineteen Nmts have been identified from 15 species (see supplemental material for alignments plus a phylogenetic analysis). Genetic studies have established the essential requirement for Nmt in a number of these species. The Saccharomyces cerevisiae genome contains a single NMT gene. A nmt1 null allele causes recessive lethality (23). Arabidopsis thaliana contains two NMT genes. Forced expression of Nmt1 cRNA produces stunted growth and reduced survival of transgenic plants (24). A null mutation of Drosophila melanogaster dNMT results in embryonic lethality (25). Mutant embryos display a range of phenotypes, including morphogenetic abnormalities associated with disordered cell movement and widespread apoptosis. Some of these changes phenocopy changes produced by genetic manipulations affecting D. melanogaster N-myristoylproteins involved in dynamic rearrangements of the actin cytoskeleton, e.g. non-receptor tyrosine kinases (Dsrc42A, Dsrc64B). Finally, a NMT null allele causes lethality in the two principal causes of systemic fungal infections in immunocompromised humans, Candida albicans and Cryptococcus neoformans (26, 27).

Three mammalian species (human, mouse, Bos taurus) each possess two Nmts (termed type I and type II (28)). Type I Nmts show a high degree of conservation across species, as do the orthologous type II Nmts. Type I and II Nmts are most divergent at their N termini (see alignment in the supplemental material). Glover et al. (29) reported that the extended N-terminal domain of type I human Nmt may be involved in targeting the enzyme to the ribosome but is not required for activity in vitro. The divergent N-terminal domains of the two Nmt isoforms may allow differential cellular localization, thereby effecting co-translational ribosome-based or post-translational cytosol-based protein acylation.

	Nmt Is a Therapeutic Target

TOP INTRODUCTION Myristoyl-CoA:Protein N-... Nmt Is a Therapeutic... Kinetic Studies of S.... Reaction Mechanism of Nmt Prospectus REFERENCES

Nmt represents an attractive therapeutic target given its requirement for the survival of several human pathogens. Different classes of Nmt inhibitors have been identified including analogs of myristate and myristoyl-CoA (30-36), myristoylpeptide derivatives (2, 37), and histidine analogs (38). All studied Nmts exhibit a preference for myristoyl-CoA. However, they have divergent peptide substrate specificities. Therefore, peptide derivatives offer an opportunity to generate species-selective inhibitors. A large library of peptidomimetics has been developed through depeptidization of an octapeptide representing the N-terminal sequence of a known yeast Nmt substrate, Arf2p (GLYASKLS, i.e. Ref. 39). Some members of this compound library have fungistatic or fungicidal activity against C. albicans and C. neoformans (40-42).

	Kinetic Studies of S. cerevisiae Nmt1p

TOP INTRODUCTION Myristoyl-CoA:Protein N-... Nmt Is a Therapeutic... Kinetic Studies of S.... Reaction Mechanism of Nmt Prospectus REFERENCES

S. cerevisiae Nmt (Nmt1p) is the best studied of the known Nmts. It is a monomer with no known co-factor requirements or post-translational modifications. Nmt1p is highly selective for myristoyl-CoA in vitro and in vivo. In vitro kinetic studies of synthetic peptides derived from the N-terminal sequences of known N-myristoylproteins have produced a set of empiric rules for identifying candidate substrates. The following criteria, based on these empiric rules, were used to search the S. cerevisiae genome data base for known or putative Nmt substrates: (a) Gly absolutely required at the +1 position; (b) charged residues, aromatics and Pro not allowed at +2; (c) all amino acids allowed at +3 and +4; (d) Ser, Thr, Ala, Gly, Cys, or Asn permitted at +5; and (e) all but Pro allowed at +6. Seventy-one ORFs (1% of the total) were identified. Among these proteins, there was a marked preference for Ser at position +5 (37/71) and for Lys at +6 (16/71).

Steady state kinetic, isothermal titration calorimetric, and x-ray crystallographic studies (43-45) all support the conclusion that Nmt1p follows an Ordered Bi Bi reaction mechanism. The apo-enzyme binds myristoyl-CoA to form a Nmt1p·myristoyl-CoA binary complex that is competent to acquire peptide substrates. Conversion of the enzyme·substrate complex to the enzyme·product complex (chemical transformation) is followed by release of CoA and then myristoylpeptide. Pre-steady state kinetic analyses indicate that the rate-determining step occurs after the chemical transformation, i.e. the rate of chemical transformation is 50-200-fold faster than the overall rate, depending upon the peptide substrate (46). Measuring enzymatic rates in the presence of increasing buffer microviscosity (47), as well as structural studies of Nmt1p complexed with substrates and substrate analogs (45), suggest that this step corresponds to a conformational change that allows product release (see below).

	Reaction Mechanism of Nmt

TOP INTRODUCTION Myristoyl-CoA:Protein N-... Nmt Is a Therapeutic... Kinetic Studies of S.... Reaction Mechanism of Nmt Prospectus REFERENCES

Structural studies of Nmt have provided insights about how it catalyzes N-myristoylation through a direct nucleophilic addition-elimination reaction. The x-ray structure of C. albicans apo-Nmt has been determined to 2.45-Å resolution (48), as have the structures of an S. cerevisiae Nmt1p·myristoyl-CoA binary complex (2.2 Å (45)) and two ternary complexes: Nmt1p·S-(2-oxo)pentadecyl-CoA·SC-58272 (2.9 Å (49)) and Nmt1p·S-(2-oxo)pentadecyl-CoA·GLYASKLA (2.5 Å (45)). S-(2-oxo)pentadecyl-CoA is a non-hydrolyzable myristoyl-CoA analog with a methylene group interposed between the reactive thioester carbonyl and sulfur (30). It is a potent competitive inhibitor of S. cerevisiae Nmt1p (K_i = 5 nM) that binds to the apo-enzyme with a similar thermodynamic signature as myristoyl-CoA (44). SC-58272 is a potent competitive peptidomimetic inhibitor (K_i = 43 nM) derived from the Arf2p-related octapeptide substrate GLYASKLA. SC58272 retains two elements critical for recognition (Ser, Lys) but replaces the N-terminal GLYA with a 2-methylimidazole plus a rigidified carbon linker (p-(2-methylimidazole-N-butyl)phenylacetyl) and the C-terminal LA with cyclohexylethyl (39).

The Nmt1p fold consists of a saddle-shaped -sheet flanked by  helices. There is pseudo-2-fold symmetry. The N-terminal half forms the myristoyl-CoA binding site. The C-terminal half forms the bulk of the peptide binding site (Fig. 1A). Each half has a fold similar to the core structure of GNAT superfamily members (22). Residues 1-54 in C. albicans apo-Nmt and 1-33 in the binary and ternary Nmt1p complexes are disordered.

View larger version (42K): [in this window] [in a new window]   Fig. 1.   Stereo ribbon diagrams of the structure of Nmt1p showing conformational changes induced by substrate binding. A, ternary complex of S. cerevisiae Nmt1p·S-(2-oxo)pentadecyl-CoA·GLYASKLA, with myristoyl-CoA modeled in place of S-(2-oxo)pentadecyl-CoA. Secondary structure code:  helices, aqua; 310 helices, purple;  strands, green; loops, brown. Atom color code: oxygen, red; phosphorus, pink; carbon, silver; nitrogen, purple; sulfur, yellow. Adapted from Ref. 45. B and C, comparison of the S. cerevisiae binary Nmt1p·myristoyl-CoA complex (yellow) with C. albicans apo-Nmt (magenta). Two major conformational changes occur with myristoyl-CoA binding: ordering of residues 34-55 with formation of a 310 helix (A') (panel B); movement of the Ab loop to open the "lid" to the peptide binding site (panel C). D, comparison of the S. cerevisiae binary complex (yellow) with the S. cerevisiae ternary complex (green). The "lid" (Ab loop) closes upon binding of peptide.

Myristoyl-CoA Binding-- Binding of myristoyl-CoA to apo-Nmt1p induces two conformational changes: (a) formation of a 3₁₀ helix (A') from part of the disordered N terminus to complete the myristoyl-CoA binding site (Fig. 1B) and (b) a change in the loop connecting helix A and strand b to open a "lid" overlying the peptide binding site (see Ab loop in Fig. 1C). The pantetheine of CoA forms an important part of this peptide binding site (Fig. 2C).

View larger version (64K): [in this window] [in a new window]   Fig. 2.   Stereo ribbon diagrams showing details of substrate binding to Nmt1p. A, myristoyl-CoA binding site. B-D, peptide binding site occupied by GLYASKLA. Note that in panel D the Gly-1 amine has been rotated 180° around  in accord with the proposed mechanism for its nucleophilic attack on the thioester carbonyl. Adapted from Ref. 45.

Bound myristoyl-CoA has a conformation resembling a question mark (Fig. 2A). As described below, this conformation may facilitate product release. The thioester carbonyl of myristoyl-CoA is H-bonded to the backbone amides of Phe-170 and Leu-171 (Fig. 2A). These two residues, positioned in a bulge in  strand e, form an oxyanion hole that polarizes the carbonyl. (Oxyanion holes are present at analogous positions in other GNATs; see Protein Data Bank accession numbers 1CJW, 1QSN, 1BO4 and Ref. 22.)

Nmtlp uses the elements that produce bends at C-1 and C-6 of myristate, as well as the floor of its acyl-CoA binding pocket, as key landmarks to measure and properly position myristoyl-CoA. The binding site structure indicates that the two additional methylenes of palmitoyl-CoA could not be accommodated without affecting positioning of its C-1 carbonyl in the oxyanion hole.

Kinetic studies of stopped flow tryptophan fluorescence reveal that myristoyl-CoA binding occurs as a two-step process (46). The fast phase is most likely diffusion-controlled. The slow phase is independent of myristoyl-CoA concentration and most likely represents the rate of formation of the N-terminal 3₁₀ A' helix.

Peptide Binding-- Nmt can be distinguished from other GNAT family members by the remarkable diversity of its peptide substrates. The only reported structural information about interactions between a Nmt and its peptide substrates comes from the ternary structure with bound Arf2p-derived GLYASKLA. Gly-1 is positioned 6.3 Å from the thioester carbonyl of myristoyl-CoA in the 2.5-Å resolution structure, a distance that can be shortened by 2 Å after rotation around  (see Fig. 2, C and D, plus the discussion of catalytic mechanism below). The environment around Gly-1 provides several H-bond interactions; the Gly-1 nitrogen is 2.9 Å from the OT1 atom of Leu-455, 3.9 Å from the O hydroxyl of Thr-205, and 4.2 Å from the O atom of Asn-169 (Fig. 2, B and C).

Contacts between the side chain of Leu-2 of the peptide and pantetheine of myristoyl-CoA complete formation of the peptide binding site and at the same time generate a 90^o bend in the peptide backbone, turning it away from myristoyl-CoA and toward a peptide binding groove (Fig. 2B). Leu is accommodated in a hydrophobic pocket. Replacing Leu with Ala in GLYASKLA results in a ~10-fold reduction in the chemical transformation rate, suggesting that this residue is important in positioning the reactive Gly-1 amine (47).

Tyr-3 is accommodated in an aromatic cluster composed of tyrosines from the active site of Nmt whereas Ala-4 lies in a large hydrophobic pocket that could accommodate uncharged residues (Fig. 2B). Ser-5, which is greatly preferred in yeast N-myristoylproteins, is H-bonded to the side chain of His-221, as well as the backbone amides of Asp-417 and Gly-418 (Fig. 2B). Lys-6, also preferred in yeast N-myristoylproteins, is H-bonded to the side chain of Asp-417, whereas its aliphatic portion is coordinated by the phenyl rings of Phe-111 and Phe-234 and the aliphatic component of Arg-107 (Fig. 2B).

The structural basis for observed differences in the peptide substrate specificities of orthologous yeast/fungal and human Nmts remains to be defined. The residues described above in S. cerevisiae Nmt1p that interact with GLYASKLA are highly conserved. However, Phe-334 and Ile-347, which form part of a hydrophobic pocket involved in coordination of Ala-4 in GLYASKLA, are represented by Ser and Ala, respectively, in the two human Nmts. This suggests that human Nmt could accommodate bulkier and/or more polar residues at position +4 of its substrates.

Kinetic studies of stopped flow tryptophan fluorescence have shown that binding of peptide substrate to the binary Nmt1p·acyl-CoA complex is a single-step process that is most likely diffusion-controlled (46). Binding leads to a change in the conformation of the Ab loop that serves to close the "lid" on the peptide binding site (Arg-107, Phe-111 interact with the aliphatic portion of Lys-6 (Figs. 1D and 2B)). In the ternary complex of Nmt1p containing SC58272, the Ab loop forms additional contacts with the dipeptide inhibitor. This suggests that the extent of ordering of the Ab loop may correlate with the overall catalytic efficiency of different Nmt1p substrates. SC58272 presumably functions as a potent inhibitor, at least in part, because it is able to form a tight, dead-end complex with extensive contacts with the Ab loop. These observations have implications for designing future species-selective inhibitors (see below).

Chemical Transformation-- Structural studies, combined with pre-steady state and steady state kinetic analyses of site-directed Nmt1p mutants (47) have identified several elements in the active site of the enzyme that facilitate the myristoyl transfer reaction. The proposed reaction is illustrated by a movie available in the supplemental material. The oxyanion hole, formed by the backbone amides of Phe-170 and Leu-171, polarizes the reactive carbonyl of bound myristoyl-CoA prior to subsequent nucleophilic attack by the N-terminal Gly-1 of a peptide substrate. The C-terminal carboxylate of Leu-455, positioned within 2.9 Å from the N-terminal Gly nitrogen of the acceptor peptide, functions as the catalytic base that deprotonates the Gly ammonium to a nucleophilic amine. Removal of the C-terminal Met-454, Leu-455 of Nmt1p results in a 300-400-fold reduction in the chemical transformation rate and converts the rate-limiting step of the enzyme from a step after chemical transformation to the transformation itself (47). In other GNAT members, a side chain carboxylate functions as a catalytic base to facilitate nucleophilic attack of a primary amino group on the thioester carbonyl of acetyl-CoA (50), although this role is assumed by the backbone carbonyl of Asn-134 in S. cerevisiae glucosamine-6-phosphate N-acetyltransferase 1 (51).

A 180-Å rotation of the Gly-1 amine along  reduces the distance between it and the thioester carbonyl of myristoyl-CoA from 6.3 to 4.3 Å (Fig. 2, C and D). H-bonding interactions between the Gly-1 amine, Asn-169, and Thr-205 position the amine along the reaction trajectory and facilitate nucleophilic attack. The oxyanion hole together with the H-bonding network formed by Asn-169 and Thr-205 stabilize the developing tetrahedral intermediate. Subsequent collapse of the tetrahedral intermediate leads to extrusion of CoA. During this process, the Gly1 amine is deprotonated, whereas the thiolate leaving group of CoA is re-protonated, presumably through proton exchange between these two groups (see the movie in supplemental material). The thiolate leaving group is stabilized by the N-6 amine of the CoA adenine. This intramolecular stabilization mechanism is economical and accounts for the bent conformation of CoA; a globular compact CoA should facilitate diffusion from the active site.

Steady state kinetics studies, performed with increasing amounts of microviscogen, combined with the x-ray crystallographic studies of the binary and ternary Nmt complexes suggest that the rate-limiting step in the reaction is an isomerization step. The isomerization could involve reversal of the changes that occur upon myristoyl-CoA binding, i.e. disordering of the N-terminal 3₁₀ A' helix and altering the conformation of the Ab loop.

	Prospectus

TOP INTRODUCTION Myristoyl-CoA:Protein N-... Nmt Is a Therapeutic... Kinetic Studies of S.... Reaction Mechanism of Nmt Prospectus REFERENCES

Defining the details of the rate-limiting step of Nmt will require additional kinetic as well as structural (e.g. NMR) studies. The information gleaned may provide new leads for designing Nmt inhibitors useful for manipulating protein N-myristoylation in various cell types, model organisms, and/or pathogens. Bi-substrate analogs that exploit the shared preference of orthologous Nmts for myristoyl-CoA and their divergent peptide substrate specificities may yield useful species-selective agents. Selectivity and potency may be enhanced by incorporating features that affect the conformation and dynamics of the Ab loop of the enzyme.

A key but unresolved question is how Nmt acquires its substrates within cells and whether this process involves additional protein partners. The discovery of two Nmt isoforms with divergent N termini raises the possibility that this domain may affect enzyme activity by regulating recognition or interactions with substrates or the intracellular location of Nmt.

	ACKNOWLEDGEMENTS

We thank George Gokel and Maurine Linder for very helpful comments and Herb Chiang for producing the movie of the proposed mechanism of Nmt.

	FOOTNOTES

^* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. Work cited from our laboratory was funded by National Institutes of Health Grant AI38200.

The on-line version of this article (available at http://www.jbc.org) contains a comparison of orthologous Nmts and a movie of the proposed catalytic mechanism.

^§ Supported in part by Medical Scientist Training Grant GM07200.

To whom correspondence should be addressed. E-mail: jgordon@molecool.wustl.edu.

Published, JBC Papers in Press, August 29, 2001, DOI 10.1074/jbc.R100042200

	ABBREVIATIONS

The abbreviation used is: Nmt, N-myristoyltransferase.

	REFERENCES

TOP INTRODUCTION Myristoyl-CoA:Protein N-... Nmt Is a Therapeutic... Kinetic Studies of S.... Reaction Mechanism of Nmt Prospectus REFERENCES

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