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Zucker Fettsäuren Nukleinsäuren Aminosäuren Rädler / Mathias SS2011 Monomer/ Oligomere Polymer/Aggregat Glucose, Polysaccharide Energie, Zellmarker Strukturbausteine Lipide, Fett Membranen Energiespeicher Kompartmentisierung ATP, cAMP RNA, DNA Energie, Signalsubstanzen Informationsspeicher Peptide Proteine, Hormone Enzyme. Motoren, molekulare Erkennung 1 Ribosomale Proteinsynthese Rädler / Mathias SS2011 •mehrere rRNA Stränge •> 50 Proteine •Durchmesser ~21nm 2 in vitro: Rädler / Mathias SS2011 3 Coupling Efficiency Vs. Peptide Length Peptide Length Coupling Efficiency 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 0.995 0.98 0.96 0.93 0.91 0.89 0.86 0.84 0.82 0.80 0.78 0.76 0.74 0.73 0.71 Rädler / Mathias SS2011 Coupling Coupling Coupling Efficiency Efficiency Efficiency 0.99 0.95 0.91 0.87 0.83 0.79 0.75 0.71 0.67 0.63 0.60 0.58 0.55 0.53 0.50 0.98 0.92 0.83 0.75 0.68 0.62 0.56 0.50 0.45 0.41 0.37 0.34 0.30 0.27 0.25 0.97 0.89 0.76 0.65 0.56 0.48 0.41 0.36 0.30 0.26 0.22 0.19 0.17 0.14 0.12 0.96 0.85 0.69 0.56 0.46 0.38 0.31 0.25 0.20 0.17 0.14 0.11 0.09 0.07 0.06 4 Rädler / Mathias SS2011 5 Rädler / Mathias SS2011 6 Different graphical representations of the same protein Rädler / Mathias SS2011 7 Faltungsproblem Mother nature has no folding probem, but we do! Konformation eines Proteins als Random Walk: Gitter-Modell: Kleines Protein mit 100 Aminosäuren => Mögliche Konformationen: 3100≈ 1030 Interne Dynamik typ ns ⇒Zeit, um alle möglichen Kombinationen durchzuspielen ≈ 1021 s Vergleiche: Alter des Universums ≈ 1020 s ! Rädler / Mathias SS2011 8 Rädler / Mathias SS2011 9 Protein Folding Related Diseases Rädler / Mathias SS2011 10 10 Rädler / Mathias SS2011 11 11 Proteinfunktionen • • • • • • • Zellgerüst Motoren Sensoren Photosynthese Enzymatische Katalyse Ionenkanäle ..... Rädler / Mathias SS2011 12 Beispiel: Die Sehkaskade Stäbchenzelle Rädler / Mathias SS2011 13 Rädler / Mathias SS2011 Proc Natl Acad Sci U S A. 2002 April 30; 99(9): 5982–5987. 14 Rädler / Mathias SS2011 15 Rädler / Mathias SS2011 16 Photozyklus Rädler / Mathias SS2011 17 Rädler / Mathias SS2011 18 Rädler / Mathias SS2011 19 Rädler / Mathias SS2011 20 Chemical modifications and processing alter the biological activity of proteins Rädler / Mathias SS2011 21 Rädler / Mathias SS2011 22 M 567/ 568 Lö 27, 28, 31 Rädler / Mathias SS2011 23 Lö 28 Rädler / Mathias SS2011 24 Rädler / Mathias SS2011 25 Disulfidbrücken stabilisieren Proteine (können in seltenen Fällen auch Knoten bilden) HUMAN AGOUTI RELATED PROTEIN Rädler / Mathias SS2011 26 Rädler / Mathias SS2011 27 Lö 38 Rädler / Mathias SS2011 28 Lö 28 Rädler / Mathias SS2011 29 Rädler / Mathias SS2011 30 Rädler / Mathias SS2011 31 Table 3-2. Covalent and Noncovalent Chemical Bonds Strength (kcal/mole)* Bond Type Length (nm) In Vacuum In Water Covalent Ionic Hydrogen van der Waals attraction (per atom) 0.15 0.25 0.30 0.35 90 80 4 0.1 90 3 1 0.1 *. The strength of a bond can be measured by the energy required to break it, here given in kilocalories per mole (kcal/mole). ( One kilocalorie is the quantity of energy needed to raise the temperature of 1000 g of water by 1C. An alternative unit in wide use is the kilojoule, kJ, equal to 0.24 kcal.) Individual bonds vary a great deal in strength, depending on the atoms involved and their precise environment, so that the above values are only a rough guide. Note that the aqueous environment in a cell will greatly weaken both the ionic and the hydrogen bonds between nonwater molecules (Panel 3-1, pp. 92-93). The bond length is the centerto-center distance between the two interacting atoms; the length given here for a hydrogen bond is that between its two nonhydrogen atoms. Rädler / Mathias SS2011 32 Rädler / Mathias SS2011 Steric limitations on the bond angles in a polypeptide chain. (A) Each amino acid contributes three bonds (colored red) to its polypeptide chain. The peptide bond is planar ( gray shading) and does not permit rotation. By contrast, rotation can occur about the C Œ±-C bond, whose angle of rotation is called psi (œà), and about the N-C Œ± bond, whose angle of rotation is called phi (). The R group denotes an amino acid side chain. (B) The conformation of the main-chain atoms in a protein is determined by one pair of phi and psi angles for each amino acid; because of steric collisions within each amino acid, most pairs of phi and psi angles do not occur. In this so-called Ramachandran plot, each dot represents an observed pair of angles in a protein. (B, from J. Richardson, Adv. Prot. Chem. 34:174-175, 1981.) 33 Rädler / Mathias SS2011 Lovell et al. 2003 Proteins 50:437 34 Glyzin, Pre-Prolin, Prolin Rädler / Mathias SS2011 BMC Struct Biol. 2005; 5: 14. doi: 0.1186/1472-6807-5-14. 35 A β−sheet is a common structure formed by parts of the polypeptide chain in globular proteins. At the top, a domain of 115 amino acids from an immunoglobulin molecule is shown; it consists of a sandwich-like structure of two β− sheets, one of which is drawn in color. At the bottom, a perfect antiparallel β− sheet is shown in detail, with the amino acid side chains denoted R. Note that every peptide bond is hydrogen-bonded to a neighboring peptide bond. The actual sheet structures in globular proteins are usually less regular than the β− sheet shown here, and most sheets are slightly twisted Rädler / Mathias SS2011 36 An α-helix is another common structure formed by parts of the polypeptide chain in proteins. (A) The oxygen-carrying molecule myoglobin (153 amino acids long) is shown, with one region of α- helix outlined in color. (B) A perfect α- helix is shown in outline. (C) As in the β-sheet, every peptide bond in an α- helix is hydrogen-bonded to a neighboring peptide bond. Note that for clarity in (B) both the side chains [which protrude radially along the outside of the helix and are denoted by R in (C)] and the hydrogen atom are omitted on the α- carbon atom of each amino acid Rädler / Mathias SS2011 37 Rädler / Mathias SS2011 38 Motifs are regular combinations of secondary structures A coiled coil motif is formed by two or more helices wound around one another e.g. Collagen Rädler / Mathias SS2011 39 Three levels of organization of a protein. The three-dimensional structure of a protein can be described in terms of different levels of folding, each of which is constructed from the preceding one in hierarchical fashion. These levels are illustrated here using the catabolite activator protein (CAP), a bacterial gene regulatory protein with two domains. When the large domain binds cyclic AMP, it causes a conformational change in the protein that enables the small domain to bind to a specific DNA sequence. The amino acid sequence is termed the primary structure and the first folding level the secondary structure. As indicated under the brackets at the bottom of this figure, the combination of the second and third folding levels shown here is commonly termed the tertiary structure, and the fourth level (the assembly of subunits) the quaternary structure of a protein Rädler / Mathias SS2011 40 The information for protein folding is encoded in the sequence Rädler / Mathias SS2011 41 Primary and secondary structure in hemagglutinin Rädler / Mathias SS2011 42 Tertiary and quaternary structure in hemagglutinin Rädler / Mathias SS2011 43 Up To Date No Unified Folding Theory Rädler / Mathias SS2011 44 Folding Funnel Rädler / Mathias SS2011 45 Folding of proteins in vivo is promoted by chaperones Rädler / Mathias SS2011 46