A minimum folding unit in the ankyrin repeat protein p16 INK4 1 1Edited by C. R. Matthews

Zhang, Bin; Peng, Zheng Yu

doi:10.1006/jmbi.2000.3803

Cited by 75 publications

(74 citation statements)

References 39 publications

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“…In the transition state for kinetic folding and unfolding, the two C-terminal ARs were fully folded while the other two ARs at the N-terminus were mainly unstructured. This conclusion was further reinforced by a study using truncated p16 proteins, which demonstrated that the two ARs at the C-terminus can form a relatively stable, autonomously folded structure while the two ARs at the N-terminus were unstructured (23). These findings suggest that the ARs at the C-terminus fold first, forming a "core" structure to facilitate the folding of the ARs at the N-terminus.…”

Section: Folding and Stabilitymentioning

confidence: 95%

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: 95%

Ankyrin Repeat: A Unique Motif Mediating Protein−Protein Interactions

2006

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“…In a more quantitative dissection, p16 INK4A (four ankyrin repeats) was divided into two parts, and the C-terminal two-repeat fragment was shown to be folded and marginally stable, although the N-terminal fragment was not [74]. Further subdivision of the C-terminal fragment into single repeats led to complete unfolding.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 96%

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…For both p16 INK4A and Notch, observed folding pathways correspond to low energy routes connecting the denatured and native states. For p16 INK4A , the C-terminal folding pathway corresponds to the lowest energy substructure determined by deletion analysis [74]. For Notch, the early-folding central repeats correspond to a low energy channel through the landscape ( Figure 4A [65,76]).…”

mentioning

confidence: 99%

“…In contrast, in bulk studies, destabilization is brought about by a uniformly-acting potential like denaturant or increased temperature, and partial unfolding of one region does not relieve the destabilization resulting on other regions. Because fragments of repeat proteins are known to be stable [74,76], the persistence of stably folded fragments in the wake of partial forced-unfolding transitions should not be unexpected.Since interfaces between ankyrin repeats are highly stabilizing, whereas individual repeats are unstable, the most likely scenario for forced unfolding is one in which individual repeats peel off in steps from a block of folded repeats. In this scenario, forced unfolding studies should identify the minimal number of repeats that can remain folded from the number of single-repeat transitions, as well as from the contour length increment produced in the last transition.…”

mentioning

confidence: 99%

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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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A minimum folding unit in the ankyrin repeat protein p16 INK4 1 1Edited by C. R. Matthews

Cited by 75 publications

References 39 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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