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For protein Engineering

For protein Engineering

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Beta Beta Presentation Transcript

  • Beta structures
  • Beta Structures
    • Functionally the most diversely populated group (antibodies, enzymes, transport proteins etc…)
    • Second biggest group of protein domain structures (after  )
    • Built up from four to over ten beta strands
    •  strands are arranged in predominantly antiparallel fashion
    • Usually two beta sheets are formed, which pack each against other, resembling barrel or distorted barrel (=double  sandwich)
  • Beta Structures
    • Anti-parallel  strands are usually arranged in two  -sheets that pack against each other and form a distorted barrel structure, the core of the structure.
    • Depending on the way the  -strands around the barrel are connected along the polypeptide chain, they can be divided into four major groups:
      • Up-and-down barrel
      • Greek Key barrel
      • Jelly roll barrel
      •  -helix
  • Up-and-down barrels
    • Schematic and topological diagrams of an up-and-down  barrel.
    • The eight  strands are all antiparallel to each other and are connected by hairpin loops.
    • Beta strands that are adjacent in the amino acid sequence are also adjacent in the three-dimensional structure of up-and-down barrels.
  • Retinol-binding protein (rbp)
    • The structure of human plasma retinol-binding protein (RBP) is an up-and-down  barrel. A retinol molecule, vitamin A (yellow), is bound inside the barrel, between the two  sheets, such that its only hydrophilic part (an OH tail) is at the surface of the molecule .
  • Retinol binding site in rbp
    • Hydrophobic part fits in a hydrophobic pocket
    • Hydroxyl group exposed to solvent
    OH
  • Alterating patterns in amino acid sequence of rbp
    • Amino acid sequence of  strands 2, 3, and 4 in human plasma retinol-binding protein.
    • The sequences are listed in such a way that residues which point into the barrel are aligned.
    • These hydrophobic residues are shown by arrows and are colored green. The remaining residues are exposed to the solvent. Hydrophobic amino acids are facing the core
    • Polar, charged and a few small hydrophobic are exposed to the solvent
  • Up-and-down barrels can contain more than 8 strands
    • Porin monomer from Rhodobacter has 14  strands
  •  propeller in neuraminidase
    • Influenza virus protein, involved in virion release from cells
    • Tetrameric protein, one monomer consists of 6 up-and down  sheets
    • Builds a propeller-like structure
  • Neuraminidase tetramer
  • Active site in  -propeller proteins
    • On the top of propeller there are extensive loops
    • The loops form active site
  • Greek Key Motifs
    • This motif is formed when one of the connections of four antiparallel  strands is not a hairpin connection.
    • The motif occurs when strand number n is connected to strand n + 3 (a) or n - 3 (b) instead of n + 1 or n - 1 in an eight-stranded antiparallel  sheet or barrel. The two different possible connections give two different hands of the Greek key motif.
    • In all protein structures known so far, only the hand shown in (a) has been observed.
  • The Fold of IgG Domains
    • Beta strands labeled A-G of the constant and variable domains of immunoglobulins have the same topology and similar structures. There are two extra  strands, C' and C'' (red) in the variable domain. The loop between these strands contains the hyper-variable region CDR2. The remaining CDR regions are at the same end of the barrel in the loops connecting  strands B and C and strands F and G.
  • Gamma Crystallin Domain
    • Found in lenses of your eyes
    • The domain structure of  -crystallin is built up from two  sheets of four antiparallel  strands, sheet 1 from  strands 1, 2, 4, and 7 and sheet 2 from strands 3, 5, 6, and 8.
    • It is obvious that the  strands are arranged in two Greek key motifs, one (red) formed by strands 1 - 4 and the other (green) by strands 5 - 8.
  • Complete  -crystallin Molecule
    • The two domains of the complete molecule have the same topology; each is composed of two Greek key motifs that are joined by a short loop region.
    • There is a greater amino acid sequence homology between the domains than the motifs within each domain, suggesting that the four Greek Key motifs in  -crystallin are evolutionarily related by gene duplication and fusion.
  • Evidence for two gene duplication events in  -crystallin evolution
    • Two domains have about 40% sequence identity
    • Two motifs within the domain share 20-30% sequence identity
    1. 2. x 2 x 2
  • Jelly Roll Mo tifs
    • The eight  strands are drawn as arrows along two edges of a strip of paper. The strands are arranged such that strand 1 is opposite strand 8, etc..
    • The  strands follow the surface of the barrel and the loop regions provide the connections at both ends of the barrel.
  • Arrangement of  strands in jelly roll barrel
  • Two Greek key motifs in jelly-roll barrel
  • Jelly-roll barrel in viruses
    • Very common in subunits of spherical viruses
    • Barrel is distorted and with helices instead of some loops
    • Example: Rhinovirus (common cold)
  • The Globular Head of the Hemagglutinin Subunit is a Distorted Jelly Roll Structure
    •  strand 1 contains a long insertion, and  strand 8 contains a bulge in the corresponding position. Each of these two strands is therefore subdivided into shorter  strands. The loop region between  strands 3 and 4 contains a short  helix, which forms one side of the receptor binding site (yellow circle).
  • Comparison of all those  -barrels Up-and-down  -crystallin-like jelly-roll
  • Beta helix
    • Two different kinds – two-sheet helix and three-sheet helix
    • Both represent deviations from idealized structure with a single spiral-like strand
  • Two-sheet  helix.
    • The two parallel  sheets are colored green and red, the loop regions that connect the  strands are yellow.
    • Each structural unit is composed of 18 residues with 9 consensus sequence Gly-Gly-X-Gly-X-Asp-X-U-X forming a  -loop-  -loop structure, where U is a large hydrophobic residue, often Leu.
    • Each loop region contains six residues of sequence Gly-Gly-X-Gly-X-Asp where X is any residue. Calcium ions are bound to both loop regions.
    Extracellular bacterial proteinase
  • Sequence pattern in two sheet beta helix X 7 U 8 X 9 X 7 U 8 X 9
    • Gly-Gly-X-Gly-X-Asp-X-U-X
    • X=any amino acid
    • U=big hydrophobic, often Leu
    • Ca ions sit in between loops
    • Motif present in several bacterial proteases
  • Three-sheet  Helix
    • As shown in (a), two of the  sheets (blue and yellow) are parallel to each other and are perpendicular to the third (green). In (b), each structural unit is composed of three  strands connected by three loop regions (labeled a, b and c).
    • Loop a (red) is invariably composed of only two residues, whereas the other two loop regions vary in length .
    • Unlike two-sheet beta helices, there are no repetitive sequence patterns