The Tolerance of a Modular Protein to Duplication and Deletion of Internal Repeats

Tripp, Katherine W.; Barrick, Doug

doi:10.1016/j.jmb.2004.09.038

Cited by 48 publications

(50 citation statements)

References 41 publications

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“…DOI: 10.1371/journal.pcbi.0020114.g005 domains in the middle are likely to disrupt the tertiary/ quaternary structure. However, duplication in the middle of a repeat does not necessarily affect the stability of the protein [21]. For most of the domain families, a similar distribution of duplication positions was found even if a few families differed.…”

Section: Repeats Often Expand In the Middlementioning

confidence: 78%

“…Internal duplications may take place in all proteins, but it is likely that such duplications are lost if the protein does not contain domains that have a repeat-forming characteristic. On the other hand, an increase in the number of repeated domains might not alter the protein structure drastically and can actually promote protein stability [21,27]. The rapid expansion of repeats in eukaryotes and the duplications of identical segments several times in tandem suggest that a specific mechanism for their expansion could exist.…”

Section: Final Discussionmentioning

confidence: 99%

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Expansion of protein domain repeats

Björklund¹,

Ekman²,

Elofsson³

2005

PLoS Comp Biol

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Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not wellunderstood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e.g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

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Section: Repeats Often Expand In the Middlementioning

confidence: 78%

Section: Final Discussionmentioning

confidence: 99%

Expansion of protein domain repeats

Björklund¹,

Ekman²,

Elofsson³

2005

PLoS Comp Biol

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“…The role of topology in the energy landscape of ankyrin repeat proteins has recently been investigated by a simplified structure-based model. 15 The equilibrium folding behavior 16,17 and a kinetic on-pathway intermediate 18 have been experimentally characterized for the Drosophila Notch receptor and variants with different number of repeats. However, a much more detailed understanding of the folding and unfolding mechanism is essential to shed light on the stabilizing factors of AR proteins, especially in view of the increasing interest in their application in biotechnology.…”

Section: 12mentioning

confidence: 99%

Characterization and Further Stabilization of Designed Ankyrin Repeat Proteins by Combining Molecular Dynamics Simulations and Experiments

Interlandi

Wetzel

Settanni

et al. 2008

Journal of Molecular Biology

110

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“…The highly cooperative and symmetrical structure allowed annotation of fold determinant features independent of evolutionary influence. While the de novo TIM barrel is a novel protein with no close native homologs, the (β/α) 8 barrel is still a native fold. Going further, the constraints associated with repeat proteins, namely the internal symmetry and the very simple secondary structure organization within a unit, make repeat proteins a platform for addressing the fundamental question of whether nature has covered most of the fold space.…”

Section: Structure Based Designmentioning

confidence: 99%

“…Repeat protein's limited interactions to only neighboring repeats also presents significantly less complexity compared to designing globular proteins where long-range contacts are abundant and often irregular. Repeat units can be inserted, removed or replaced without significantly affecting the overall structure as long as the compatible interfaces between units are present [8]. Indeed, the intended goal of designing repeat proteins is to create modular systems from which custom scaffolds can be created for various applications [7].…”

Section: Introductionmentioning

confidence: 99%

Designing repeat proteins: a modular approach to protein design

Parmeggiani

Huang

2017

Current Opinion in Structural Biology

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms Abstract Repeat proteins present unique opportunities for engineering because of their modular nature that potentially allows LEGO Ⓡ like construction of macromolecules. Nature takes advantage of these properties and uses this type of scaffold for recognition, structure, and even signaling purposes. In recent years, new protein modeling tools facilitated the design of novel repeat proteins, creating possibilities beyond naturally occurring scaffolds alone. We highlight here the different design strategies and summarize the various structural families and novel proteins achieved. Introduction A goal of protein engineers is to understand how sequence and structure features contribute to the makeup of proteins. However, polypeptide complexity and variability complicate the analysis of these features. Proteins that carry distinct patterns of repetitive sequences (and therefore structural features) are ideal systems with reduced complexity to inform our understanding of proteins. These repeat proteins are widespread in nature [1] and the evolutionary process that created them is quite remarkable: a segment of sequence that is structurally compatible with itself is duplicated in tandem, and the connected segments diverge to accommodate new functions within the tolerance of structural compatibility [2]. Splicing and duplication of genes govern the highly efficient and economic ways -by which higher order structures are built from recycling and repeating basic modules -to engineer structurally coupled functions. As a consequence, the repeated segments that make up a repeat protein are often not identical. However, the modularity inspires engineering efforts. In this review, we discuss the methods developed for designing repeat proteins, their achievements, and the new directions ahead.

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The Tolerance of a Modular Protein to Duplication and Deletion of Internal Repeats

Cited by 48 publications

References 41 publications

Expansion of protein domain repeats

Expansion of protein domain repeats

Characterization and Further Stabilization of Designed Ankyrin Repeat Proteins by Combining Molecular Dynamics Simulations and Experiments

Designing repeat proteins: a modular approach to protein design

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