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Dissertation Mechanism and dynamics of acyl-CoA mediated protein lysine acylation in mitochondria Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Naturwissenschaftlichen Fakultät I – Biowissenschaften – der Martin-Luther-Universität Halle Wittenberg, vorgelegt von Herrn Zeljko Simic geb. am 04.02.1982 in Bajina Basta Gutachter: Prof. Dr. Mike Schutkowski Prof. Dr. Wolfgang Sippl Prof. Dr. Dirk Schwarzer Tag der öffentlichen Verteidigung: 13.10.2016 Table of contents Abbreviations list ....................................................................................................................................... iv List of figures ............................................................................................................................................ viii List of tables ............................................................................................................................................... xi Introduction .................................................................................................................................................. 1 Lysine acetylation ................................................................................................................................... 1 Protein lysine acetylation in mitochondria .......................................................................................... 3 Induction of mitochondrial protein hyperacetylation .......................................................................... 5 Mitochondrial lysine deacetylases ....................................................................................................... 5 Mitochondrial lysine acetyltransferase ................................................................................................ 8 Proposed mechanisms of mitochondrial protein acetylation ........................................................... 8 Physiological conditions of mitochondrial matrix ............................................................................. 11 Coenzyme A and its acyl-thioester derivatives ................................................................................ 14 Acetyl-CoA ............................................................................................................................................ 16 Acyl-CoA thioesters and PTMs of proteins in mitochondria .......................................................... 19 Aim of the thesis ................................................................................................................................... 22 Materials and Methods ............................................................................................................................ 23 Chemical synthesis .............................................................................................................................. 23 Synthesis of CPS1 peptide and CPS1 peptide derivatives ....................................................... 23 Synthesis of TNFα peptide derivatives ......................................................................................... 23 Synthesis and purification of acyl-CoA derivatives ..................................................................... 24 Synthesis and purification of acetyl-adenylate (Ac-AMP) .......................................................... 24 Preparative HPLC ................................................................................................................................ 25 Analytical HPLC .................................................................................................................................... 25 Expression and purification of the enzymes .................................................................................... 25 Expression and purification of human SIRT2 .............................................................................. 25 Expression and purification of human SIRT3 and SIRT5 .......................................................... 26 Expression and purification of human SIRT4 .............................................................................. 26 Expression and purification of human CypA ................................................................................ 27 i SDS-polyacrylamide gel electrophoresis (SDS-PAGE) ................................................................. 27 Native-PAGE ......................................................................................................................................... 28 Dot-blot assay ....................................................................................................................................... 28 4CN Colorimetric detection for Dot- and Western blot assays ...................................................... 29 Western-blot .......................................................................................................................................... 29 Determination of protein concentration ............................................................................................. 30 Mass spectrometry (MS) ..................................................................................................................... 30 Sample preparation and MALDI-TOF/TOF MS ........................................................................... 30 In-gel trypsin digestion ..................................................................................................................... 31 Nano-UPLC ....................................................................................................................................... 31 ESI-QTOF-MS/MS-Analysis ........................................................................................................... 31 Capillary electrophoresis (CE) ........................................................................................................... 32 Continuous fluorescence assay for measuring sirtuin activity....................................................... 32 Fluorescence spectroscopy ................................................................................................................ 33 Circular dichroism spectroscopy (CD) .............................................................................................. 33 Peptide microarray ............................................................................................................................... 33 Results ....................................................................................................................................................... 35 Non-enzymatic lysine acetylation of model peptide using Ac-CoA .............................................. 35 Kinetic and thermodynamic parameters of non-enzymatic lysine acetylation ............................ 37 Non-enzymatic acylation of CPS1 peptide by different acyl-CoA thioesters .............................. 41 Modulation of non-enzymatic lysine acetylation .............................................................................. 42 Small molecules ............................................................................................................................... 42 Water content and ionic strength ................................................................................................... 43 The methylation of N-Ɛ-amino group of lysine residue ............................................................... 45 Non-enzymatic acetylation of CypA .................................................................................................. 47 Non-enzymatic succinylation of CypA ............................................................................................... 53 Activity of acylated CypA ..................................................................................................................... 56 Structural alterations of acylated CypA ............................................................................................. 57 Desuccinylation of succinylated CypA by mitochondrial sirtuins .................................................. 58 Acylation of CypA as a function of the lysine pKa values ............................................................... 61 Shift of acylation type by simultaneous action of SIRT3 and Succ-CoA ..................................... 63 Expanding acyl specificity of SIRT4 .................................................................................................. 65 ii Enzymatic lysine acetylation ............................................................................................................... 68 Citrate synthase ................................................................................................................................ 68 Acetyl-CoA acetyltransferase, mitochondrial ............................................................................... 69 Hydroxymethylglutaryl-CoA synthase, mitochondrial ................................................................. 69 Carnitine O-acetyltransferase ......................................................................................................... 69 Acetyl-CoA synthetase .................................................................................................................... 70 Diamine acetyltransferase 1 ........................................................................................................... 73 Protein
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