Biochemistry - Metamorphic proteins

MRC Centre for Protein Engineering, Hills Road, Cambridge CB2 0QH, UK.
Science (Impact Factor: 31.48). 07/2008; 320(5884):1725-6. DOI: 10.1126/science.1158868
Source: PubMed

ABSTRACT Proteins that can adopt more than one native folded conformation may be more common than previously thought.

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    • "Our recent studies have revealed that the D-state consists of dynamically disordered and ordered domains, with the ordered domain stabilizing two high-energy cis peptidyl–prolyl bonds, which are trans in the Sstate [16]. Thus, IscU can be classified as a metamorphic protein [17], a protein that can adopt two different folds. This raises the questions: why has IscU evolved to be metamorphic, and do the two different conformations play physiologically important roles? "
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    ABSTRACT: IscU from Escherichia coli, the scaffold protein for iron-sulfur cluster biosynthesis and delivery, populates a complex energy landscape. IscU exists as two slowly interconverting species: one (S) is largely structured with all four peptidyl-prolyl bonds trans; the other (D) is partly disordered but contains an ordered domain that stabilizes two cis peptidyl-prolyl peptide bonds. At pH 8.0, the S-state is maximally populated at 25 °C, but its population decreases at higher or lower temperatures or at lower pH. The D-state binds preferentially to the cysteine desulfurase (IscS), which generates and transfers sulfur to IscU cysteine residues to form persulfides. The S-state is stabilized by Fe-S cluster binding and interacts preferentially with the DnaJ-type co-chaperone (HscB), which targets the holo-IscU:HscB complex to the DnaK-type chaperone (HscA) in its ATP-bound from. HscA is involved in delivery of Fe-S clusters to acceptor proteins by a mechanism dependent on ATP hydrolysis. Upon conversion of ATP to ADP, HscA binds the D-state of IscU ensuring release of the cluster and HscB. These findings have led to a more complete model for cluster biosynthesis and delivery.
    FEBS letters 01/2013; 587(8). DOI:10.1016/j.febslet.2013.01.003 · 3.34 Impact Factor
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    • "Conventionally, it is thought that proteins adopt a unique, evolutionarily conserved three-dimensional structure. More recently, a small but growing number of ''metamorphic'' proteins, capable of reversibly transiting between two or more different-folded conformations as a result of environmental triggers, have been identified (Murzin 2008). One such family of these ''metamorphic'' proteins, capable of undergoing such reversible conformational changes, are the chloride intracellular channels (CLICs). "
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    ABSTRACT: Members of the chloride intracellular channel (CLIC) family exist primarily as soluble proteins but can also auto-insert into cellular membranes to form ion channels. While little is known about the process of CLIC membrane insertion, a unique feature of mammalian CLIC1 is its ability to undergo a dramatic structural metamorphosis between a monomeric glutathione-S-transferase homolog and an all-helical dimer upon oxidation in solution. Whether this oxidation-induced metamorphosis facilitates CLIC1 membrane insertion is unclear. In this work, we have sought to characterise the role of oxidation in the process of CLIC1 membrane insertion. We examined how redox conditions modify the ability of CLIC1 to associate with and insert into the membrane using fluorescence quenching studies and a sucrose-loaded vesicle sedimentation assay to measure membrane binding. Our results suggest that oxidation of monomeric CLIC1, in the presence of membranes, promotes insertion into the bilayer more effectively than the oxidised CLIC1 dimer.
    Biophysics of Structure and Mechanism 05/2009; 39(1):129-38. DOI:10.1007/s00249-009-0450-0 · 2.47 Impact Factor
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    ABSTRACT: Gives an overview on the principle concepts employed in the DSPL (Data Stream Processing Language) programming environment, an integrated approach to automate system design and implementation of parallel applications. The programming environment consists of a programming language and the following set of integrated tools: (1) The modeling tool automatically derives a software model from the given application program. (2) The model based optimization tool uses the software model to compute such design decisions as network topology, task granularity, task assignment and task execution order. (3) Finally, the compiler/optimizer transforms the application program into executable code for the chosen processor network, reflecting the design decisions
    Programming Models for Massively Parallel Computers, 1993. Proceedings; 10/1993
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