Recognition of Dimethylarginine Analogues by Tandem Tudor Domain Protein Spindlin1.

Miriam R B Porzberg,Laust Moesgaard,Jasmin Mecinović,Jacob Kongsted,Catrine Johansson,Udo Oppermann

doi:10.3390/molecules27030983

Abstract

Epigenetic readout of the combinatorial posttranslational modification comprised of trimethyllysine and asymmetric dimethylarginine (H3K4me3R8me2a) takes place via biomolecular recognition of tandem Tudor-domain-containing protein Spindlin1. Through comparative thermodynamic data and molecular dynamics simulations, we sought to explore the binding scope of asymmetric dimethylarginine mimics by Spindlin1. Herein, we provide evidence that the biomolecular recognition of H3K4me2R8me2a is not significantly affected when R8me2a is replaced by dimethylarginine analogues, implying that the binding of K4me3 provides the major binding contribution. High-energy water molecules inside both aromatic cages of the ligand binding sites contribute to the reader–histone association upon displacement by histone peptide, with the K4me3 hydration site being lower in free energy due to a flip of Trp151.

Highlights

Posttranslational modifications on histones are key in regulating global chromatin environments in the human genome [1,2]
We provide evidence that the biomolecular recognition of H3K4me2R8me2a is not significantly affected when R8me2a is replaced by dimethylarginine analogues, implying that the binding of K4me3 provides the major binding contribution
SAM-dependent methylation of the positively charged guanidinium group of arginine is catalysed by Protein Arginine Methyltransferases (PRMTs), of which nine are currently identified, and results in three methylation products: monomethylarginine (Rme1), symmetric dimethylarginine (Rme2s), and asymmetric dimethylarginine (Rme2a) [5]

Summary

Introduction

Posttranslational modifications on histones are key in regulating global chromatin environments in the human genome [1,2]. Among these modifications, the methylation of lysine and arginine residues in highly conserved histone tails has been extensively studied [3,4]. SAM-dependent methylation of the positively charged guanidinium group of arginine is catalysed by Protein Arginine Methyltransferases (PRMTs), of which nine are currently identified, and results in three methylation products: monomethylarginine (Rme1), symmetric dimethylarginine (Rme2s), and asymmetric dimethylarginine (Rme2a) [5]. Dimethylarginine binding reader proteins contain Tudor domains possessing aromatic cages that associate with the positively charged guanidinium group through a combination of cation–π interactions and π–π stacking [10,11,12,13]. Sap3in0dklDina hisoamssoodciimateerdcwomithpotusemdoor-f itgherneeesSispainn/dShsatys bdeoemnafionusn[d14to]. bSephinigdhlilny1exisparessssoecdiaitnedvawriiothustuhmumoraingecnaensciesracnedllsh, ainscblueednifnogunbrdeatost,boevhairgiahnly, aenxdprceoslosendcainncvearr[i1o5u,s16h].uFmuarnthecarmncoerre,cSelplsin, dinlicnlu1dstiinmgublareteasstr,RoNvAarieaxn-, parnedsscioolnonancdanacfeferc[t1s5W,16n]t.-sFiugrntahlelirnmgo[r1e4,,1S7p]i.nTdhlieno1vsetrimalluslatrtuesctruRrNe oAf eSxppinredslsinio1nisasnidmailfafercttos oWthnetr-sTigundaollrindgo[m14a,i1n7]p.rTohteeinosv,earsaltlhsetrSupctiun/rSesotyf Sdpoimndaliinns cisonsitmaiinlaβr-tboaorrthelerfoTluddsotrhadtofmoramin tpwrooteairnosm, aastitchpeoScpkient/sSesntyabdlionmgabininsdcionngtatoinaβ1-0b-amrreerl fHo3ldKs4tmhaet3Rfo8rmmet2waopaerpotmidaetiwc ipthocakeKtds oefn4a5blninMg b(Finigduinreg 1toa)a[1104-]m. er H3K4me3R8me2a peptide with a Kd of 45 nM (Figure 1a) [14]

Methods

Results

Conclusion