Equilibrium Folding and Stability of Myotrophin: A Model Ankyrin Repeat Protein

Mosavi, Leila K.; Williams, Suzanna; Peng, Zhengyu

doi:10.1016/s0022-2836(02)00441-2

Cited by 54 publications

(52 citation statements)

References 34 publications

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“…Furthermore, no partially folded intermediates have been found in these equilibrium folding-unfolding reactions, except that a NMR study of p19 in the presence of moderate concentrations of urea revealed the possible existence of an equilibrium intermediate with poor chemical shift dispersions, suggesting that it is largely unfolded (32). Taken together, these findings indicate that like globular proteins, the equilibrium folding and unfolding of AR proteins is highly cooperative (17,22,38).…”

Section: Folding and Stabilitymentioning

confidence: 90%

“…Moreover, hydrogen bonding between the hydroxyl group of Thr and the imidazole ring of His contributes to the stability of AR motif and global AR proteins (16) (Figure 1c). The Val/IleVal-Xxx (hydrophilic)-Leu/Val-Leu-Leu motif (positions [17][18][19][20][21][22] is the central piece of the second R-helix of an AR motif, and it functions to form intra-and inter-AR hydrophobic networks to stabilize the global sketch of an AR protein (5,8). In addition, glycine residues are conserved at positions 13 and 25, which terminate the helices and provide the freedom for a loop to link both helices (5).…”

Section: Structurementioning

confidence: 99%

“…Hence, one might think that AR proteins differ from globular proteins in folding and stability and each AR in a protein could unfold and refold individually. However, folding studies on INK4 proteins (12,17,23,32,33), Notch AR domain (34,35), myotrophin (22), and some engineered AR proteins (14,15,36,37) have demonstrated that AR proteins exhibit an equilibrium two-state transition between native and unfolded proteins by spectroscopic and calorimetric criteria, similar to most globular proteins. Furthermore, no partially folded intermediates have been found in these equilibrium folding-unfolding reactions, except that a NMR study of p19 in the presence of moderate concentrations of urea revealed the possible existence of an equilibrium intermediate with poor chemical shift dispersions, suggesting that it is largely unfolded (32).…”

Section: Folding and Stabilitymentioning

confidence: 99%

“…On the basis of sequence consensus analyses, a novel design strategy was successfully developed to construct combinatorial AR protein libraries to select novel specific binders. In this approach (15), a consensus sequence of the AR module derived from 2220 AR sequences was designed with seven less-conserved positions (1,3,10,22,25) randomly filled by various amino acids (for position 26, H, N, or Y; for the other six positions, any amino acid but not G, C, or P) to generate libraries containing different AR modules. Subsequently, these AR modules were linked randomly to form AR proteins containing multiple AR modules.…”

Section: Consensus Design and Combinatorial Library Of Arsmentioning

confidence: 99%

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Ankyrin Repeat: A Unique Motif Mediating Protein−Protein Interactions

2006

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Ankyrin repeat, one of the most widely existing protein motifs in nature, consists of 30−34 amino acid residues and exclusively functions to mediate protein−protein interactions, some of which are directly involved in the development of human cancer and other diseases. Each ankyrin repeat exhibits a helix−turn−helix conformation, and strings of such tandem repeats are packed in a nearly linear array to form helix−turn−helix bundles with relatively flexible loops. The global structure of an ankyrin repeat protein is mainly stabilized by intra- and inter-repeat hydrophobic and hydrogen bonding interactions. The repetitive and elongated nature of ankyrin repeat proteins provides the molecular bases of the unique characteristics of ankyrin repeat proteins in protein stability, folding and unfolding, and binding specificity. Recent studies have demonstrated that ankyrin repeat proteins do not recognize specific sequences, and interacting residues are discontinuously dispersed into the whole molecules of both the ankyrin repeat protein and its partner. In addition, the availability of thousands of ankyrin repeat sequences has made it feasible to use rational design to modify the specificity and stability of physiologically important ankyrin repeat proteins and even to generate ankyrin repeat proteins with novel functions through combinatorial chemistry approaches.

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Section: Folding and Stabilitymentioning

confidence: 90%

Section: Structurementioning

confidence: 99%

Section: Folding and Stabilitymentioning

confidence: 99%

Section: Consensus Design and Combinatorial Library Of Arsmentioning

confidence: 99%

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Ankyrin Repeat: A Unique Motif Mediating Protein−Protein Interactions

2006

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“…Coincidence of such probes supports an all-or-none transition between the native (N) state and denatured (D) ensemble. More recently, another four-ankyrin-repeat protein, myotrophin, has also been shown to satisfy the spectroscopic test for cooperative equilibrium two-state unfolding, and displays an appropriately high m-value in urea denaturation [50].…”

Section: Cooperative Equilibrium Folding Of Repeat Proteinsmentioning

confidence: 99%

Repeat-protein folding: New insights into origins of cooperativity, stability, and topology

Kloss

Courtemanche

Barrick

2008

Archives of Biochemistry and Biophysics

101

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Although our understanding of globular protein folding continues to advance, the irregular tertiary structures and high cooperativity of globular proteins complicates energetic dissection. Recently, proteins with regular, repetitive tertiary structures have been identified that sidestep limitations imposed by globular protein architecture. Here we review recent studies of repeat-protein folding. These studies uniquely advance our understanding of both the energetics and kinetics of protein folding. Equilibrium studies provide detailed maps of local stabilities, access to energy landscapes, insights into cooperativity, determination of nearest-neighbor interaction parameters using statistical thermodynamics, relationships between consensus sequences and repeat-protein stability. Kinetic studies provide insight into the influence of short-range topology on folding rates, the degree to which folding proceeds by parallel (versus localized) pathways, and the factors that select among multiple potential pathways. The recent application of force spectroscopy to repeat-protein unfolding is providing a unique route to test and extend many of these findings. KeywordsRepeat-protein; Ankyrin repeat; protein folding; energy landscape; atomic force microscopy In the last twenty-five years, advances in experimental studies and in computation and theory have greatly improved our understanding of protein folding. On the experimental side, advances have come from new and improved techniques, including site-directed mutagenesis, hydrogen exchange (HX) methods, improvements to rapid mixing devices, and development of single-molecule fluorescence and force spectroscopy. Experimental advances have also come in the form of generalizations and insights from expanding databases of thermodynamic and kinetic constants for protein folding [1][2][3][4][5].On the computational side, advances in our understanding of protein folding have come from huge increases in computer speed and storage capacity, in innovative methods to study energetics of folding such as ensemble-based approaches and replica exchange methods [6,7], and distributed computing methods [8]. As with experiment, computational studies of folding, and in particular, fold prediction, have greatly benefited from expanding databases of protein structure [9,10]. On the theoretical side, the application of ideas from condensed-matter *Correspondence: barrick@jhu.edu, (410) 516-0409. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptArch Biochem Biophys. Author manuscript; available in PMC 2009 January ...

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Consensus Design of Repeat Proteins

2004

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Consensus design is a valuable protein-engineering method that is based on statistical information derived from sequence alignments of homologous proteins. Recently, consensus design was adapted to repeat proteins. We discuss the potential of this novel repeat-based approach for the design of consensus repeat proteins and repeat protein libraries and summarize recent results from such experiments.

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Equilibrium Folding and Stability of Myotrophin: A Model Ankyrin Repeat Protein

Cited by 54 publications

References 34 publications

Ankyrin Repeat: A Unique Motif Mediating Protein−Protein Interactions

Ankyrin Repeat: A Unique Motif Mediating Protein−Protein Interactions

Repeat-protein folding: New insights into origins of cooperativity, stability, and topology

Consensus Design of Repeat Proteins

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