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.
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October 2015
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Review Article|
October 09 2015
Dissecting and reprogramming the folding and assembly of tandem-repeat proteins
Pamela J.E. Rowling;
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;
Elin M. Sivertsson
*Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
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Albert Perez-Riba;
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;
Ewan R.G. Main
1
†School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, U.K.
1Correspondence may be addressed to either author (emaile.main@qmul.ac.uk and lsi10@cam.ac.uk).
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Laura S. Itzhaki
Laura S. Itzhaki
1
*Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
1Correspondence may be addressed to either author (emaile.main@qmul.ac.uk and lsi10@cam.ac.uk).
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Publisher: Portland Press Ltd
Received:
May 13 2015
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2015 Authors; published by Portland Press Limited
2015
Biochem Soc Trans (2015) 43 (5): 881–888.
Article history
Received:
May 13 2015
Citation
Pamela J.E. Rowling, Elin M. Sivertsson, Albert Perez-Riba, Ewan R.G. Main, Laura S. Itzhaki; Dissecting and reprogramming the folding and assembly of tandem-repeat proteins. Biochem Soc Trans 1 October 2015; 43 (5): 881–888. doi: https://doi.org/10.1042/BST20150099
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