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Exploring the Folding Energy Landscape of a Series of Designed Consensus Tetratricopeptide Repeat Proteins

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Exploring the Folding Energy Landscape of a Series of Designed Consensus Tetratricopeptide Repeat Proteins PHYSICS, BIOPHYSICS AND COMPUTATIONAL BIOLOGY BIOPHYSICS AND COMPUTATIONAL BIOLOGY Correction for ‘‘The role of fluctuations and stress on the Correction for ‘‘Exploring the folding energy landscape of a effective viscosity of cell aggregates,’’ by Philippe Marmottant, series of designed consensus tetratricopeptide repeat proteins,’’ Abbas Mgharbel, Jos Ka¨fer,Benjamin Audren, Jean-Paul Rieu, by Yalda Javadi and Ewan R. G. Main, which appeared in issue Jean-Claude Vial, Boudewijn van der Sanden, Athanasius F. M. 41, October 13, 2009, of Proc Natl Acad Sci USA (106:17383– Mare´e, Franc¸ois Graner, and He´le`ne Delanoe¨-Ayari, which 17388; first published October 1, 2009; 10.1073/pnas. appeared in issue 41, October 13, 2009, of Proc Natl Acad Sci 0907455106). USA (106:17271–17275; first published September 25, 2009; The authors note that, due to a printer’s error, some text 10.1073/pnas.0902085106). appeared incorrectly on page 17384. In the left column, the The authors note that, due to a printer’s error, the affiliation second sentence in the third full paragraph, ‘‘This yielded [D]50% for Abbas Mgharbel, Benjamin Audren, Jean-Paul Rieu, and (midpoint of unfolding) and mD-N (change in solvent-accessible ⌬ H2O ⌬ H2O He´le`ne Delanoe¨-Ayari at Universite´ de Lyon appeared incor- surface area upon protein unfolding) from which GD–N/ G03j rectly in part. The name of the authors’ laboratory, Laboratoire (free energy of unfolding in water) was calculated (Table S1),’’ Mate´riaux et Phe´nome`nes Quantiques, should instead have should instead have appeared as ‘‘This yielded [D]50% (midpoint appeared as Laboratoire de Physique de la Matie`re Condense´e of unfolding) and mD-N (change in solvent-accessible surface ⌬ H2O et Nanostructures. The corrected affiliation line appears below. area upon protein unfolding) from which GD–N (free energy of unfolding in water) was calculated (Table S1).’’ In the right a b ¨ a Philippe Marmottant , Abbas Mgharbel , Jos Kafer , column, the sentence beginning on line 17, ‘‘All of the values of b b a Benjamin Audren , Jean-Paul Rieu , Jean-Claude Vial , ⌬ H2O ⌬ H2O GD–N/ G03j calculated are within error for urea and GuHCl Boudewijn van der Sandenc, Athanasius F. M. Mare´ ed, denaturations,’’ should instead have appeared as ‘‘All of the a,e b ⌬ H2O Franc¸ois Graner , and He´ le` ne Delanoe¨ -Ayari values of G03j calculated are within error for urea and GuHCl denaturations.’’ These errors do not affect the conclusions of the aLaboratoire de Spectrome´trie Physique, Unite´Mixte de Recherche 5588, Universite´Grenoble I and Centre National de la Recherche Scientifique, 140 article. Avenue de la Physique, F-38402 Martin d’He`res Cedex, France; bLaboratoire de Physique de la Matie`re Condense´e et Nanostructures, Centre National www.pnas.org/cgi/doi/10.1073/pnas.0911552106 de la Recherche Scientifique, Unite´Mixte de Recherche 5586, Universite´de Lyon, Universite´Lyon 1, 43 Boulevard du 11 novembre 1918, F-69622 Villeurbanne Cedex, France; cInstitut des Neurosciences Grenoble, Institute National de la Sante´et de la Recherche Me´dicale U836, Chemin Fortune´ Ferrini, BP 170, F-38042 Grenoble Cedex 9, France; dTheoretical Biology/Bioinformatics, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; and eBiologie du De´veloppement, Unite´Mixte de Recherche 3215 Institut Curie and Centre National de la Recherche Scientifique, Institut National de la Sante´et de la Recherche Me´dicale U934, 26 Rue d’Ulm, F-75248 Paris Cedex 05, France www.pnas.org/cgi/doi/10.1073/pnas.0911892106 19204 ͉ www.pnas.org Downloaded by guest on September 29, 2021 Exploring the folding energy landscape of a series of designed consensus tetratricopeptide repeat proteins Yalda Javadi and Ewan R. G. Main1 Centre for Structural and Chemical Biology, Department of Chemistry and Biochemistry, University of Sussex, Falmer near Brighton BN1 9QJ, United Kingdom Edited by Peter G. Wolynes, University of California, San Diego, La Jolla, CA, and approved August 18, 2009 (received for review July 8, 2009) Repeat proteins contain short, tandem arrays of simple structural 16). Recently, these studies have been complemented by folding motifs (20؊40 aa). These stack together to form nonglobular simulations that show and predict that the cooperativity of structures that are stabilized by short-range interactions from repeat protein folding decouples on increasing repeat number or residues close in primary sequence. Unlike globular proteins, they where high local frustration occurs (17–19). have few, if any, long-range nonlocal stabilizing interactions. One Designed consensus repeat proteins provide an excellent ubiquitous repeat is the tetratricopeptide motif (TPR), a 34-aa system for investigating the fundamental properties of repeat helix-turn-helix motif. In this article we describe the folding kinet- proteins, because each repeat has identical intra- and inter- ics of a series of 7 designed TPR proteins that are assembled from repeat interactions. Thus, designed repeat proteins are more arraying identical designed consensus repeats (CTPRan). These structurally symmetric than natural repeat proteins and can range from the smallest 2-repeat protein to a large 10-repeat easily be extended or shortened by adding or removing whole protein (Ϸ350 aa). In particular, we describe how the energy repeats. This ability provides a unique and exquisitely tuneable landscape changes with the addition of repeat units. The data perturbation that differs radically from normal amino acid reveal that although the CTPRa proteins have low local frustration, mutations and enables a wider exploration of repeat protein their highly symmetric, modular native structure is reflected in folding energy landscapes. For example, dependence of stability, their multistate kinetics of unfolding and folding. Moreover, al- folding rate, cooperativity, and thus folding pathway on repeat though the initial folding of all CTPRan proteins involves a nucleus number can be explored by engineering a series of proteins that with similar solvent accessibility, their subsequent folding to the increase in size through addition of identical consensus motifs. native structure depends directly on repeat number. This corre- In particular, we and the Regan laboratory have used 2 series of sponds to an increasingly complex landscape that culminates in designed consensus TPRs (a 34-aa, helix-turn-helix motif), called CTPRa10 populating a misfolded, off-pathway intermediate. These CTPR and CTPRa proteins, to investigate the dependence of results extend our current understanding of the malleable folding thermodynamic characteristics and denatured state on increas- pathways of repeat proteins and highlight the consequences of ing repeat number (Fig. 1; the 2 series only differ by a 2-aa adding identical repeats to the energy landscape. substitution per repeat) (20–23). These studies have highlighted the 1-dimensionality and changing equilibrium properties of design protein ͉ kinetic traps ͉ misfolding ͉ protein folding increasing repeat number by showing that the thermodynamic unfolding transition can be described and, importantly, predicted by an Ising model that uses nearest-neighbor interactions within epeat proteins consist of tandem arrays of simple structural a 1-dimensional lattice (22). Such a description implies that motifs that consist of 20–40 residues. These modules stack R thermodynamically, individual repeats unfold independently of together to form elongated, nonglobular protein folds. They are each other and thus can populate partially folded configurations. highly abundant, widespread in nature and, second only to This observation was confirmed when Cortajarena et al. used immunoglobulins, are the most common protein class to spe- equilibrium, NMR-detected hydrogen/deuterium exchange to cialize in protein–protein interactions (1). Examples of repeat observe sequential unfolding transitions for 2 CTPR proteins proteins include tetratricopeptide (TPR), ankyrin, and leucine- containing 2 and 3 repeats, respectively (20). However, we have rich (LRR) repeats (2, 3). Unusually, unlike globular proteins, also previously shown that kinetic folding of these 2 proteins at these repeat proteins do not rely on complex long-range stabi- 20 °C was 2-state over the limited denaturant concentration lizing interactions. Instead their recurring modular architectures range measured (23). These studies have been further comple- are dominated by regularized short-range interactions (both mented by folding simulations showing that although the CTPRs inter- and intrarepeat). This distinctive feature, which results in possess very low inter- and intrarepeat frustration, their coop- a quasi–1-dimensional structure, has made them extremely erativity of folding as interpreted by correlation length is roughly attractive targets as models for protein folding and design 3 repeats (18). studies. In this study we investigated the kinetic folding cooperativity The keen interest in repeat proteins has led to successful and folding energy landscapes on increasing repeat protein protein design of consensus TPR (4), ankyrin (5, 6), and LRR length by comparing the folding kinetics of the largest series of proteins (7) and extensive stability and folding studies on natural highly symmetric designed repeat proteins to date. This consists ␤ ankyrin repeat proteins (a 33-residue repeat that forms a -turn of 7 designed CTPRa proteins that range from 2.5 to 10.5 repeats ␣ followed by 2 antiparallel -helices) (8–14). These
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