MYRbase: analysis of genome-wide glycine myristoylation enlarges the functional spectrum of eukaryotic myristoylated proteins

Maurer‐Stroh, Sebastian; Gouda, Masaki; Novatchkova, Maria; Schleiffer, Alexander; Schneider, Georg; Sirota, Fernanda L.; Wildpaner, Michael; Hayashi, Nobuhiro; Eisenhaber, Frank

doi:10.1186/gb-2004-5-3-r21

Cited by 82 publications

(45 citation statements)

References 159 publications

(115 reference statements)

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“…Among the sequences with functional annotation, the overwhelming number of hits has fit expectations [10,15,[41][42][43]. A few, singular false-positive predictions might be excusable but what about whole protein families predicted to have the sequence signal without any supporting biological context, for example with inappropriate subcellular localization or proteins of species that do not have the necessary enzymes?…”

Section: The Issue Of Hidden Sequence Signalsmentioning

confidence: 91%

“…The linker region can also contain determinants that enhance membrane binding. Among these membrane-attachment factors, there are clusters of positively charged residues or palmitoylatable cysteines in close vicinity to the attachment position of the primary lipid anchor [15]. The amino acid types required for these functions generally do fulfill the conditions for good linker properties.…”

Section: The Sequence Motifs Coding For Myris-toylation Farnesylatiomentioning

confidence: 98%

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Posttranslational Modifications and Subcellular Localization Signals: Indicators of Sequence Regions without Inherent 3D Structure?

Eisenhaber

2007

CPPS

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Given the huge number of sequences of otherwise uncharacterized protein sequences, computer-aided prediction of posttranslational modifications (PTMs) and translocation signals from amino acid sequence becomes a necessity. We have contributed to this multi-faceted, worldwide effort with the development of predictors for GPI lipid anchor sites, for N-terminal N-myristoylation sites, for farnesyl and geranylgeranyl anchor attachment as well as for the PTS1 peroxisomal signal. Although the substrate protein sequence signals for various PTMs or translocation systems vary dramatically, we found that their principal architecture is similar for all the cases studied. Typically, a small stretch of the amino acid residues is buried in the catalytic cleft of the protein-modifying enzyme (or the binding site of the transporter). This piece most intensely interacts with the enzyme and its sequence variability is most restricted. This stretch is surrounded by linker segments that connect the part bound by the enzyme with the rest of the substrate protein. These residues are, as a trend, small with a flexible backbone and polar. Due to the mechanistic requirements of binding to the enzyme, we suggest that most PTM sites are necessarily embedded into intrinsically disordered regions (except for cases of autocatalytic PTMs, PTMs executed in the unfolded state or non-enzymatic PTMs) and this issue requires consideration in structural studies of proteins with complex architecture. Surprisingly, some proteins carry sequence signals for posttranslational modification or translocation that remain hidden in the normal biological context but can become fully functional in certain conditions.

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Section: The Issue Of Hidden Sequence Signalsmentioning

confidence: 91%

Section: The Sequence Motifs Coding For Myris-toylation Farnesylatiomentioning

confidence: 98%

Posttranslational Modifications and Subcellular Localization Signals: Indicators of Sequence Regions without Inherent 3D Structure?

Eisenhaber

2007

CPPS

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“…As previous experience with a similar project (the application of the MyrPS/NMT myristoylation predictor [11,12] for searching the nonredundant database and the resulting MYRbase [13]) has shown, large-scale scans produce a considerable number of hits, and, for their ranking with respect to the biological significance, additional criteria are necessary. It should be noted that the score function of PrePS tests the concordance of C-termini of query proteins (the terminal 12 residues) with a simplified binding site model of the respective prenyltransferase without consideration of other sequence properties.…”

Section: Introductionmentioning

confidence: 99%

“…It should be noted that the score function of PrePS tests the concordance of C-termini of query proteins (the terminal 12 residues) with a simplified binding site model of the respective prenyltransferase without consideration of other sequence properties. It is not rare that sites for posttranslational modifications and sequence motifs coding for subcellular translocation are not conserved among proteins with otherwise highly similar sequences (exemplary cases of myristoylation [13], GPI lipid anchoring [14], and prenylation [15]). More surprisingly, functional motifs can be hidden in proteins without the proper biological context and be masked by other sequence signals (e.g., the case of peroxisomal targeting signal type 1 (PTS1) in proteins destined for other subcellular localizations [16]).…”

Section: Introductionmentioning

confidence: 99%

Towards Complete Sets of Farnesylated and Geranylgeranylated Proteins

et al. 2007

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Three different prenyltransferases attach isoprenyl anchors to C-terminal motifs in substrate proteins. These lipid anchors serve for membrane attachment or protein–protein interactions in many pathways. Although well-tolerated selective prenyltransferase inhibitors are clinically available, their mode of action remains unclear since the known substrate sets of the various prenyltransferases are incomplete. The Prenylation Prediction Suite (PrePS) has been applied for large-scale predictions of prenylated proteins. To prioritize targets for experimental verification, we rank the predictions by their functional importance estimated by evolutionary conservation of the prenylation motifs within protein families. The ranked lists of predictions are accessible as PRENbase (http://mendel.imp.univie.ac.at/sat/PrePS/PRENbase) and can be queried for verification status, type of modifying enzymes (anchor type), and taxonomic distribution. Our results highlight a large group of plant metal-binding chaperones as well as several newly predicted proteins involved in ubiquitin-mediated protein degradation, enriching the known functional repertoire of prenylated proteins. Furthermore, we identify two possibly prenylated proteins in Mimivirus. The section HumanPRENbase provides complete lists of predicted prenylated human proteins—for example, the list of farnesyltransferase targets that cannot become substrates of geranylgeranyltransferase 1 and, therefore, are especially affected by farnesyltransferase inhibitors (FTIs) used in cancer and anti-parasite therapy. We report direct experimental evidence verifying the prediction of the human proteins Prickle1, Prickle2, the BRO1 domain–containing FLJ32421 (termed BROFTI), and Rab28 (short isoform) as exclusive farnesyltransferase targets. We introduce PRENbase, a database of large-scale predictions of protein prenylation substrates ranked by evolutionary conservation of the motif. Experimental evidence is presented for the selective farnesylation of targets with an evolutionary conserved modification site.

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“…[6][7][8] Myristoylation is required for full expression of the biological function of these proteins, ensuring conformational stability and the ability to interact with membranes or the hydrophobic domains of other proteins. [9][10][11] Nmt performs this critical function in the eukaryotic cell and is essential for the in vitro viability of many species of fungi, including Candida albicans and Cryptococcus neoformans, which are both medically important.…”

mentioning

confidence: 99%

FTR1335 Is a Novel Synthetic Inhibitor of Candida albicans N(-)Myristoyltransferase with Fungicidal Activity

Ebara

Naito

Nakazawa

et al. 2005

Biological & Pharmaceutical Bulletin

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Fungal infections range in severity from common superficial problems affecting the skin and nails, to deeply invasive and disseminated infections, such as systemic candidiasis and pulmonary aspergillosis.1,2) These illnesses reduce the quality of life of patients and can progress to become life threatening. Four classes of antifungal drugs are available at present: polyene macrolides, azoles, flucytosine and candins. However, their use is restricted by their limited activity spectra, toxicity, hazardous interactions and non-optimal pharmacokinetics.

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MYRbase: analysis of genome-wide glycine myristoylation enlarges the functional spectrum of eukaryotic myristoylated proteins

Cited by 82 publications

References 159 publications

Posttranslational Modifications and Subcellular Localization Signals: Indicators of Sequence Regions without Inherent 3D Structure?

Posttranslational Modifications and Subcellular Localization Signals: Indicators of Sequence Regions without Inherent 3D Structure?

Towards Complete Sets of Farnesylated and Geranylgeranylated Proteins

FTR1335 Is a Novel Synthetic Inhibitor of Candida albicans N(-)Myristoyltransferase with Fungicidal Activity

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