Computational design of a leucine-rich repeat protein with a predefined geometry

Rämisch, Sebastian; Weininger, Ulrich; Martinsson, Jonas; Akke, Mikael; André, Ingemar

doi:10.1073/pnas.1413638111

Cited by 53 publications

(40 citation statements)

References 37 publications

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“…The Yersinia LRR proteins are also attractive in evolutionary and structural biology due to their wide distribution among bacterial and eukaryotic cells, the highly conserved repeat consensus, and the varied number of tandem repeat copies (51,52). It is clear that Yersinia chromosomally and plasmid-encoded LRR proteins originated from two different ancestors.…”

Section: Discussionmentioning

confidence: 99%

Distribution and Evolution of Yersinia Leucine-Rich Repeat Proteins

Huang

Hui

et al. 2016

Infect Immun

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c Leucine-rich repeat (LRR) proteins are widely distributed in bacteria, playing important roles in various protein-protein interaction processes. In Yersinia, the well-characterized type III secreted effector YopM also belongs to the LRR protein family and is encoded by virulence plasmids. However, little has been known about other LRR members encoded by Yersinia genomes or their evolution. In this study, the Yersinia LRR proteins were comprehensively screened, categorized, and compared. The LRR proteins encoded by chromosomes (LRR1 proteins) appeared to be more similar to each other and different from those encoded by plasmids (LRR2 proteins) with regard to repeat-unit length, amino acid composition profile, and gene expression regulation circuits. LRR1 proteins were also different from LRR2 proteins in that the LRR1 proteins contained an E3 ligase domain (NEL domain) in the C-terminal region or an NEL domain-encoding nucleotide relic in flanking genomic sequences. The LRR1 proteinencoding genes (LRR1 genes) varied dramatically and were categorized into 4 subgroups (a to d), with the LRR1a to -c genes evolving from the same ancestor and LRR1d genes evolving from another ancestor. The consensus and ancestor repeat-unit sequences were inferred for different LRR1 protein subgroups by use of a maximum parsimony modeling strategy. Structural modeling disclosed very similar repeat-unit structures between LRR1 and LRR2 proteins despite the different unit lengths and amino acid compositions. Structural constraints may serve as the driving force to explain the observed mutations in the LRR regions. This study suggests that there may be functional variation and lays the foundation for future experiments investigating the functions of the chromosomally encoded LRR proteins of Yersinia.

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Section: Discussionmentioning

confidence: 99%

Distribution and Evolution of Yersinia Leucine-Rich Repeat Proteins

Huang

Hui

et al. 2016

Infect Immun

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“…Tremendous efforts have been made to engineer protein tandem repeats based on naturally occurring modules34353637383940 or de novo computational modules4142. In most cases, the engineered protein tandem repeats display exceptionally high thermal and/or chemical stabilities compared to their ancestry building modules due to favourable enthalpic gains from inter-modular interactions and entropic stabilisation through covalent loop linkages3437394143.…”

Section: Discussionmentioning

confidence: 99%

Protein knotting through concatenation significantly reduces folding stability

Hsu

2016

Sci Rep

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Concatenation by covalent linkage of two protomers of an intertwined all-helical HP0242 homodimer from Helicobacter pylori results in the first example of an engineered knotted protein. While concatenation does not affect the native structure according to X-ray crystallography, the folding kinetics is substantially slower compared to the parent homodimer. Using NMR hydrogen-deuterium exchange analysis, we showed here that concatenation destabilises significantly the knotted structure in solution, with some regions close to the covalent linkage being destabilised by as much as 5 kcal mol−1. Structural mapping of chemical shift perturbations induced by concatenation revealed a pattern that is similar to the effect induced by concentrated chaotrophic agent. Our results suggested that the design strategy of protein knotting by concatenation may be thermodynamically unfavourable due to covalent constrains imposed on the flexible fraying ends of the template structure, leading to rugged free energy landscape with increased propensity to form off-pathway folding intermediates.

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“…2c). Core cysteine residues play a central role in stability and folding cooperativity were found in LRR domains (Rämisch et al 2014). Thus, LRR domains are essential for the formation of a multimer linked by disulfide bonds.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Babesia-responsive leucine-rich repeat domain-containing protein from the hard tick Haemaphysalis longicornis

et al. 2015

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Haemaphysalis longicornis is a tick known for transmitting Babesia parasites, including Babesia gibsoni, in East Asian countries. The vector tick must have strategies to control Babesia parasites, while Babesia parasites are also considered to establish an evasive mechanism from the tick's innate immunity. Due to this mutual tolerance, H. longicornis is considered to be a vector of Babesia parasites. Recent studies have shown the important roles of leucine-rich repeat (LRR) domain-containing proteins in innate immunity in many living organisms. Some LRR domain-containing proteins were identified in ticks; however, their functions are still unknown. In this study, a novel LRR domain-containing protein was identified from H. longicornis (HlLRR). HlLRR contains two LRR domains, and the expression levels of mRNA and proteins were upregulated during blood feeding, particularly in the salivary glands and midgut. In addition, recombinant HlLRR (rHlLRR) demonstrated growth inhibition activity against B. gibsoni in vitro without a hemolytic effect at any concentration used. Moreover, the diameters of Babesia merozoites treated with rHlLRR were significantly larger than those of the control group. These results strongly indicate the key roles of HlLRR in the tick's innate immunity against Babesia parasites. Furthermore, HlLRR might be a potential alternative drug to treat babesiosis.

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Computational design of a leucine-rich repeat protein with a predefined geometry

Cited by 53 publications

References 37 publications

Distribution and Evolution of Yersinia Leucine-Rich Repeat Proteins

Distribution and Evolution of Yersinia Leucine-Rich Repeat Proteins

Protein knotting through concatenation significantly reduces folding stability

Identification of the Babesia-responsive leucine-rich repeat domain-containing protein from the hard tick Haemaphysalis longicornis

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