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Repetitive, Non-Globular Proteins: Nature to Nanotechnology

Dissecting and reprogramming the folding and assembly of tandem-repeat proteins

Pamela J.E. Rowling, Elin M. Sivertsson, Albert Perez-Riba, Ewan R.G. Main, Laura S. Itzhaki
Biochemical Society Transactions Oct 09, 2015, 43 (5) 881-888; DOI: 10.1042/BST20150099
Pamela J.E. Rowling
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
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Elin M. Sivertsson
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
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Albert Perez-Riba
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
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Ewan R.G. Main
School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, U.K.
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  • For correspondence: e.main@qmul.ac.uklsi10@cam.ac.uk
Laura S. Itzhaki
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
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  • For correspondence: e.main@qmul.ac.uklsi10@cam.ac.uk
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Abstract

Studying protein folding and protein design in globular proteins presents significant challenges because of the two related features, topological complexity and co-operativity. In contrast, tandem-repeat proteins have regular and modular structures composed of linearly arrayed motifs. This means that the biophysics of even giant repeat proteins is highly amenable to dissection and to rational design. Here we discuss what has been learnt about the folding mechanisms of tandem-repeat proteins. The defining features that have emerged are: (i) accessibility of multiple distinct routes between denatured and native states, both at equilibrium and under kinetic conditions; (ii) different routes are favoured for folding compared with unfolding; (iii) unfolding energy barriers are broad, reflecting stepwise unravelling of an array repeat by repeat; (iv) highly co-operative unfolding at equilibrium and the potential for exceptionally high thermodynamic stabilities by introducing consensus residues; (v) under force, helical-repeat structures are very weak with non-co-operative unfolding leading to elasticity and buffering effects. This level of understanding should enable us to create repeat proteins with made-to-measure folding mechanisms, in which one can dial into the sequence the order of repeat folding, number of pathways taken, step size (co-operativity) and fine-structure of the kinetic energy barriers.

  • ankyrin
  • protein design
  • protein engineering
  • protein folding
  • tandem-repeat protein
  • tetratricopeptide
  • TPR

Footnotes

  • Repetitive, Non-Globular Proteins: Nature to Nanotechnology: Held at the University of York, U.K., 30 March 2015–1 April 2015.

  • Abbreviations

    ANK,
    ankyrin repeat;
    CTPRa,
    consensus TPR;
    TPR,
    tetratricopeptide repeat
    • © 2015 Authors; published by Portland Press Limited
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    October 2015

    Volume: 43 Issue: 5

    Biochemical Society Transactions: 43 (5)
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    Dissecting and reprogramming the folding and assembly of tandem-repeat proteins
    Pamela J.E. Rowling, Elin M. Sivertsson, Albert Perez-Riba, Ewan R.G. Main, Laura S. Itzhaki
    Biochemical Society Transactions Oct 2015, 43 (5) 881-888; DOI: 10.1042/BST20150099
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    Dissecting and reprogramming the folding and assembly of tandem-repeat proteins
    Pamela J.E. Rowling, Elin M. Sivertsson, Albert Perez-Riba, Ewan R.G. Main, Laura S. Itzhaki
    Biochemical Society Transactions Oct 2015, 43 (5) 881-888; DOI: 10.1042/BST20150099

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    • Article
      • Abstract
      • Repeat proteins have polarized folding mechanisms
      • The shape of the rate-limiting energy barrier reflects the repeat architecture
      • Parallel routes for folding repeat proteins
      • What folds first does not necessarily unfold last
      • Mapping the full breadth of the energy landscape of repeat proteins
      • From small to giant repeat proteins
      • Folding mechanisms made-to-measure
      • Relationship between folding and function
      • Outstanding questions
      • Future directions: repeat-protein design and assembly
      • Funding
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      • References
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    Keywords

    ankyrin
    protein design
    protein engineering
    protein folding
    tandem-repeat protein
    tetratricopeptide
    TPR

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