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  • PROTEIN  (5)
  • 1
    Keywords: PEPTIDE ; Germany ; COMMON ; INFORMATION ; TOOL ; SITE ; PROTEIN ; PROTEINS ; INDEX ; BINDING ; SEQUENCE ; SEQUENCES ; SIGNAL ; ACID ; GLYCOPROTEIN ; DESIGN ; PEPTIDES ; PARAMETERS ; STABILITY ; BEHAVIOR ; INITIATION ; GP120 ; CHAIN ; PROTEIN DESIGN
    Abstract: Certain sequences within proteins have the ability to undergo an abrupt cooperative conformational switch from beta-strand to helix in response to decreasing polarity of the environment. This behavior was first observed at the CD4 binding site of the envelope glycoprotein gp120 of HIV-1, but evidence has accumulated that polarity-driven beta --〉 alpha switches may be widespread, serving both to facilitate binding on protein/membrane or protein/protein contact and to signal that docking has occurred. The characteristics identified so far that distinguish switch sequences (a reverse turn at the N-terminus that acts as a helix initiation site, a conserved tryptophan residue downstream, and high potential for both the helix and beta-fold) appear to be necessary but not sufficient, as some otherwise promising sequences found in data bank searches proved not to be capable of cooperative refolding. Analysis of existing switches has led to the development of the side chain interaction index (SCII) as a further parameter characterizing the beta --〉 alpha polarity-driven switch. Data bank searches using this additional parameter have successfully identified a series of new potential switch sequences. All of them have in common the amino acid tetrad LPCR at the N-terminus and a tryptophan 5-20 residues C-terminal to it. Those with a high SCII as well, when synthesized and tested, exhibited strongly cooperative polarity-driven refolding. Control peptides, containing all other parameters but with a low SCII, did not. Using this new information, an artificial sequence was designed that had a high SCII as well as the initiation site, conserved tryptophan, and high P-alpha and P-beta. When synthesized and tested, this sequence did in fact behave as a conformational switch, refolding cooperatively from beta-fold to helix at a threshold value of 30% TFE. The successful design of a polarity-driven conformational switch opens the possibility of using this motif as a tool in protein engineering
    Type of Publication: Journal article published
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  • 2
    Keywords: PEPTIDE ; Germany ; COMMON ; PROTEIN ; PROTEINS ; DOMAIN ; ANTIGEN ; DYNAMICS ; SIMULATION ; SEQUENCE ; SEQUENCES ; antibodies ; antibody ; TARGET ; DESIGN ; VARIABILITY ; VACCINE ; STRATEGIES ; PREDICTION ; GP120 ; MOLECULAR-DYNAMICS ; HIV-1 ; GENOMIC DIVERSITY ; HTLV-III ; MINIMIZATION
    Abstract: The most promising target antigen for an HIV vaccine designed using the classic antibody strategy has been the viral coat protein gp120. Unfortunately, its high variability has prevented this approach. We examine here a 15-residue peptide derived from the CD4-binding domain of gp120. By use of molecular dynamics computer simulation, it is shown that despite considerable sequence variation, the three-dimensional structure of the peptide is preserved over the full range of clade-specific sequences. Furthermore, sequences threaded onto the structure exhibit common three-dimensional electrostatic and hydrophobic properties. These common physicochemical characteristics constitute a pharmacophoric footprint that promises to be useful in the design of a synthetic antigen for vaccine development
    Type of Publication: Journal article published
    PubMed ID: 15239651
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  • 3
    Keywords: PEPTIDE ; SPECTRA ; Germany ; PROTEIN ; BIOLOGY ; MOLECULAR-BIOLOGY ; FUSION ; PEPTIDES ; SECONDARY STRUCTURE ; molecular biology ; molecular ; CHEMISTRY ; methods ; USA ; SPECTRUM
    Type of Publication: Journal article published
    PubMed ID: 17320030
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  • 4
    Keywords: PEPTIDE ; RECEPTOR ; Germany ; DISTINCT ; PROTEIN ; PROTEINS ; SEQUENCE ; SEQUENCES ; DESIGN ; MEMBRANE ; FUSION ; PEPTIDES ; SERIES ; AMINO-ACIDS ; SECONDARY STRUCTURE ; DE-NOVO ; RECEPTORS ; FLEXIBILITY ; MEMBRANES ; MEMBRANE PROTEIN ; MEMBRANE-PROTEIN ; SEGMENT ; RESIDUES ; ENVIRONMENTS ; GLYCINE ; INFLUENZA HEMAGGLUTININ ; INFRARED-SPECTROSCOPY ; PROPENSITIES ; SNARE PROTEINS ; SPANNING DOMAIN ; VIRUS G-PROTEIN
    Abstract: Fusion of biological membranes is mediated by distinct integral membrane proteins, e.g., soluble N-ethylmaleimide-sensitive factor attachment protein receptors and viral fusion proteins. Previous work has indicated that the transmembrane segments (TMSs) of such integral membrane proteins play an important role in fusion. Furthermore, peptide mimics of the transmembrane part can drive the fusion of liposomes, and evidence had been obtained that fusogenicity depends on their conformational flexibility. To test this hypothesis, we present a series of unnatural TMSs that were designed de novo based on the structural properties of hydrophobic residues. We find that the fusogenicity of these peptides depends on the ratio of alpha-helix-promoting Leu and beta-sheet-promoting Val residues and is enhanced by helix-destabilizing Pro and Gly residues within their hydrophobic cores. The ability of these peptides to refold from an alpha-helical state to a beta-sheet conformation and backwards was determined under different conditions. Membrane fusogenic peptides with mixed Leu/ Val sequences tend to switch more readily between different conformations than a nonfusogenic peptide with an oligo-Leu core. We propose that structural flexibility of these TMSs is a prerequisite of fusogenicity
    Type of Publication: Journal article published
    PubMed ID: 15456911
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  • 5
    Keywords: PEPTIDE ; Germany ; PROTEIN ; PROTEINS ; MECHANISM ; BIOLOGY ; MOLECULAR-BIOLOGY ; MEMBRANE ; FUSION ; FUSION PROTEINS ; CRYSTAL-STRUCTURE ; PEPTIDES ; SECONDARY STRUCTURE ; DOMAINS ; FUSION PROTEIN ; molecular biology ; molecular ; RE ; GLYCINE ; INFLUENZA HEMAGGLUTININ ; MUTATIONAL ANALYSIS ; VIRAL MEMBRANE-FUSION ; analysis ; ENVELOPE PROTEIN ; TRANSMEMBRANE DOMAIN ; viral ; circular dichroism ; AVIAN-SARCOMA ; LEUKOSIS VIRUS ; membrane fusion ; VIRUS GLYCOPROTEIN-G
    Abstract: Membrane fusion is essential for many biological processes. Though there hove been many structure and fusion studies of cel lular and viral fusion proteins in the last years, their functional mechanism remains elusive. In particular, the structural modes of operation of the transmembrane domains and viral fusion peptides of fusion proteins during membrane fusion have not been elucidated, although work on de novo designed fusogenic peptides suggested that conformational flexibility was necessary. In addition, the use of different and incompatible measurement criteria has made a comparative overview difficult. Here, we report a systematic structural analysis of viral fusion peptides from different fusion protein classes and transmembrane domains of viral and cellular fusion proteins by using circular dichroism spectroscopy. The data that were obtained demonstrate that class viral fusion peptides show a structural flexibility between helix and irregular secondary structures, whereas fusion peptides of class II viral fusion proteins are characterized by a stable random coil and turn structure. Thus, conformational flexibility does not seem to be a universal criterion for the fusion activity of a fusion peptide. On the contrary, the transmembrane domains of fusion proteins are distinguished by a structural flexibility between helix and sheet structure that is similar to de novo designed unnatural peptides with high fusion activities (M. W. Hofmann et al. PNAS 2004, 101, 14776-14781). Thus, the conformational behavior of the fusogenic unnatural peptides most closely resembles that of, fusion protein transmembrane domains, and allows them to be used to gain a deeper understanding of the membrane fusion process
    Type of Publication: Journal article published
    PubMed ID: 18330852
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