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Deciphering Enzyme Function Using Peptide Arrays

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Abstract

Enzymes are key molecules in signal-transduction pathways. However, only a small fraction of more than 500 human kinases, 300 human proteases and 200 human phosphatases is characterised so far. Peptide microarray based technologies for extremely efficient profiling of enzyme substrate specificity emerged in the last years. This technology reduces set-up time for HTS assays and allows the identification of downstream targets. Moreover, peptide microarrays enable optimisation of enzyme substrates. Focus of this review is on assay principles for measuring activities of kinases, phosphatases or proteases and on substrate identification/optimisation for kinases. Additionally, several examples for reliable identification of substrates for lysine methyl-transferases, histone deacetylases and SUMO-transferases are given. Finally, use of high-density peptide microarrays for the simultaneous profiling of kinase activities in complex biological samples like cell lysates or lysates of complete organisms is described. All published examples of peptide arrays used for enzyme profiling are summarised comprehensively.

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Abbreviations

4Pip:

Piperidine-4-carboxylic acid

Aa:

Amino acid

Ab:

Antibody

Abl:

Abelson protein-tyrosine kinase

Abz:

2-Aminobenzoic acid

Acc:

4-Aminomethylcyclohexanecarboxylic acid

ACC:

7-Amino-4-carbamoylmethyl coumarin

ACEi:

Angiotensin converting enzyme inhibitor

Akt1:

Protein kinase B isoform 1

Amb:

4-Aminomethylbenzoic acid

ANPK:

Androgen receptor interacting nuclear protein kinase

AP:

Alkaline phosphatase

APC:

Activated protein C

Aurora A:

Breast tumour-amplified serine/threonine kinase

Aurora B:

Aurora- and IPL1-like midbody-associated protein 1, protein serine/threonine kinase

Bcl2:

Apoptosis regulator B-cell lymphoma 2

Bip:

ß-(4-Biphenyl)alanine

BMK1:

Big mitogen-activated protein kinase 1

Boc:

tert. Butyl-oxy-carbonyl

BODIPY:

(4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene) fluorophore

B-Raf:

Tyrosine kinase-like kinase of the Raf family

Bth:

ß-(3-Benzothienyl)alanine

Bz:

Benzyl

CaMK2:

Calmodulin dependent kinase 2

Cbz:

Benzyl-oxy-carbonyl protecting group

C-CAM-L:

Large isoform of cell–cell adhesion molecule

Cdc15:

Cell devision control protein 15, yeast protein kinase

Cdk2, 5:

Cyclin dependent kinase 2, 5

CDPK-1:

Calcium dependent protein kinase

cGPKIa:

cGMP dependent protein kinase Ia

Cha:

3-Cyclohexyl-alanine

Chk1, 2:

DNA damage checkpoint kinases 1 and 2

CK1, CK2:

Casein kinase 1, 2

CMV:

Cytomegalovirus

c-Raf:

Tyrosine kinase-like kinase of the Raf family

c-Src:

Sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue protein tyrosin kinase

Cy3:

3H-indolium, 2-[3-[1-[6-[(2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]-1,3-dihydro-3,3-dimethyl-5-sulfo-2H-indol-2-ylidene]-1-propen-1-yl]-1-ethyl-3,3-dimethyl-5-sulfo-, inner salt

Cy5:

3H-indolium, 2-[5-[1-[6-[(2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]-1,3-dihydro-3,3-dimethyl-5-sulfo-2H-indol-2-ylidene]-1,3-pentadien-1-yl]-1-ethyl-3,3-dimethyl-5-sulfo-, inner salt

DABCYL:

4-(Dimethylaminoazo)benzene-4-carboxylic acid

DANSyl:

Dimethylamino-naphthalen-sulphonic acid

Dap(Dnp):

2-Amino,3-(2′,4′-Dinitrophenylamino)-propionic acid

DAPK:

Death-associated protein kinase

Dbf1-Mob1:

Budding yeast protein kinase Dbf1 in complex with activator (Mps one binder 1)

Dbg:

α,α-Dibutyl glycine

DegP:

Degradation protein, serine protease HtrA

DEX:

Dexamethasone

Dok6:

Docking protein 6

DYRK1A, 2, 4:

Dual-specificity tyrosine phosphorylation-regulated kinase isoform 1A, 2 and 4

EGFR:

Epidermal growth factor receptor kinase

Elk1:

Ets like gene 1

EphA4:

Ephrin receptor tyrosine kinase isoform 4a

EphB2:

Ephrin receptor tyrosine kinase isoform B2

Erk1, Erk2:

Extracellular signal regulated kinases isoforms 1 and 2

Fes:

Feline sarcoma (Snyder-Theilen) oncogene, protein-tyrosine kinase

FGFR-1:

Fibroblast growth factor receptor 1

FITC:

Fluorescein-thiocarbamoyl

Flt3:

Fms-related tyrosine kinase 3

FRET:

Forster resonance energy transfer

Fyn:

Protein-tyrosine kinase of the Src family

GluR1:

AMPAR glutamate receptor 1

Gsk3ß:

Glycogen synthase kinase 3ß

H3, 4:

Histone 3 and 4

HD1, 2:

Histone deacetylase complexes 1 and 2 from P. sativum

Her2:

Herstatin isoform 2

proto:

Oncogenic receptor tyrosine kinase of the EGFR family

hK2:

Glandular kallikrein 2

HRP:

Horseradish peroxidase

InsR:

Insulin receptor kinase

IR:

Insulin receptor tyrosine kinase

Jak1 and 2:

Janus protein-tyrosine kinases 1 and 2

JNK1and 3:

c-Jun NH2-terminal kinases 1 and 3

KAc :

Side chain acetylated lysine

KDR:

Kinase insert domain receptor

KDRI:

Kinase insert domain receptor inhibitor

Kit:

Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue, receptor tyrosine kinase

KPI-2:

Kinase/phosphatase/inhibitor 2

Lck:

Lymphocyte cell-specific protein-tyrosine kinase

LMWPTP:

Low molecular weight protein-tyrosine phosphatase

LPS:

Lipopolysaccharid

Lyn:

Protein-tyrosine kinase of the Src family

MAF:

Mouse adult fibroblast

MALDI-TOF/MS:

Matrix-assisted laser desorption ionisation—time of flight/mass spectrometry

MAP3K8:

Mitogen-activated protein kinase 3 K8

MAPKAPK-2:

MAP kinase activated protein kinase-2

MCA:

7-Methoxycoumarin-4-yl)acetyl

MeAla:

N-methyl-alanine

MEK1:

MAP, Erk kinase 1

MELK:

Maternal leucine zipper kinase

MePhe:

N-methyl-phenylalanine

Met:

Hepatocyte growth factor receptor, protein tyrosin kinase

MK2:

Mitogen-activated protein kinase kinase 2

mLCEC:

Mouse lung capillary endothel cells

MPK1, 2, 3, 6:

Mitogen-activated protein kinases, isoforms 1,2,3, and 6

Nal:

Naphthyl-alanine

NEK6:

Never in mitosis gene A related kinase 6

NGF:

Nerve growth factor

Nle:

Norleucine

p70S6:

Ribosomal protein S6 kinase

PABP1:

Poly(A)-binding protein 1

PapA:

Fimbrial major pilin protein A

PBMC:

Peripheral blood mononuclear cell

PDE4B2, C2, A4, D5:

Isoform B2, C2, A4 and D5 of phosphodiesterase 4

PDGFRß:

Platelet-derived growth factor receptor kinase ß

PDGRF I-1:

Platelet-derived growth factor receptor inhibitor 1

PDK1:

3-Phosphoinositide dependent protein kinase 1

Pia:

4-Piperidinylacetic acid

Pim1:

Proviral integration site 1 kinase

Pin1:

Peptidyl-prolyl-cis/trans-isomerase Pin1, protein interacting with NIMA 1

Pip:

l-piperidine-2-carboxylic acid, pipecolic acid

PKA:

Protein kinase A, cAMP-dependent protein kinase

PKCζ, PKCα, PKCδ:

Protein kinase C isoforms

PKG:

Protein kinase G

PKI:

Protein kinase inhibitor

PknB:

Receptor-like protein kinase from Mycobacterium tuberculosis

Plk1, Plk3, Plk4:

Polo like kinase isoforms 1,3 and 4

PNA:

Peptide nucleic acid

POD:

Peroxidase

PP1, PP2, PP3, PP2A, PP2B:

Protein phosphatase class 1,2,3, 2A and 2B

ppGalNACT:

UDP-N-acetyl-ß-d-galactosamin:polypeptide N-acetylgalactosaminyl-transferase family

pSer:

Phospho-serine

pThr:

Phospho-threonine

PTPμ:

Protein-tyrosine phosphatase μ

PTP1B:

Protein-tyrosine phosphatase 1B

pTyr:

Phospho-tyrosine

PVDF:

Poly(vinylidene difluoride)

Pyk2:

Proline-rich tyrosine kinase 2

QSY:

Xanthylium, 9-[2-[[4-[carboxyl]-1-piperidinyl]sulfonyl]phenyl]-3,6-bis(methylphenylamino)-, chloride

Rock2:

Rho-associated kinase isoform 2

Rsk2:

Ribosomal S6 kinase isoform 2

SAMDI:

Self-assembled monolayers for matrix assisted laser desorption ionisation mass spectrometry

sec. ab:

Secondary antibody

SGK1:

Serum/glucocorticoid regulated kinase isoform 2

SHP1 and SHP2:

SH2 domain containing phosphatase 1 and 2

SIR2:

Silent information regulator 2

SMRT:

Silencing mediator of retinoic acid and thyroid hormone receptor

SNAP25:

Synaptosomal-associated protein 25

SPR:

Surface plasmon resonance

SRPK4:

SR protein kinase isoform 4

ß-Ala:

3-Aminopropionic acid

ß-Gal:

ß-Galactosidase

SSRP1:

Structure-specific recognition protein 1

STAT5:

Signal transducer and activator of transcription 5

Suc:

Succinyl

TBB:

4,5,6,7-Tetrabromobenzotriazole

TBK1:

TANK-binding kinase isoform 1

tBuGly:

α-tert. Butyl-glycine

tBuPhe:

4-tert. Butyl-phenylalanine

TCPTP:

T-cell protein-tyrosine phosphatase

Thi:

ß-(2-Thienyl)-alanine

Thz:

R-4-thiazolidine-carboxylic acid

Tic:

1,2,3,4-Tetrahydro-isochinoline-3-carboxylic acid

Tie2:

Tunica interna endothelial cell kinase 2

Tpk1:

Tyrosine protein kinase 1

TrβI and TRβII:

Transforming growth factor β receptor tyrosine kinases I and II

TSSK3:

Testis specific serine/threonine kinase 3

uPA:

Urinary plasminogen activator

VEGFR2:

Vascular endothelial growth factor receptor kinase 2

Wt:

Wildtype

Yes:

Yamaguchi sarcoma viral oncoge, protein-tyrosine kinase

Z:

Benzyl-oxy-carbonyl

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  1. Institute of Agricultural and Nutritional Sciences, Department of Human Nutrition, Martin-Luther-University Halle-Wittenberg, Von Danckelmann Platz 2, 06120, Halle, Germany

    Alexandra Thiele & Gabriele I. Stangl

  2. Institute of Biochemistry and Biotechnology, Department of Enzymology, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Strasse 3, 06120, Halle, Germany

    Mike Schutkowski

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  1. Alexandra Thiele
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Thiele, A., Stangl, G.I. & Schutkowski, M. Deciphering Enzyme Function Using Peptide Arrays. Mol Biotechnol 49, 283–305 (2011). https://doi.org/10.1007/s12033-011-9402-x

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