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The structure of the ankyrin-binding site of beta-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties.

ABSTRACT: Spectrin and ankyrin participate in membrane organization, stability, signal transduction, and protein targeting; their interaction is critical for erythrocyte stability. Repeats 14 and 15 of betaI-spectrin are crucial for ankyrin recognition, yet the way spectrin binds ankyrin while preserving its repeat structure is unknown. We have solved the crystal structure of the betaI-spectrin 14,15 di-repeat unit to 2.1 A resolution and found 14 residues critical for ankyrin binding that map to the end of the helix C of repeat 14, the linker region, and the B-C loop of repeat 15. The tilt (64 degrees) across the 14,15 linker is greater than in any published di-repeat structure, suggesting that the relative positioning of the two repeats is important for ankyrin binding. We propose that a lack of structural constraints on linker and inter-helix loops allows proteins containing spectrin-like di-repeats to evolve diverse but specific ligand-recognition sites without compromising the structure of the repeat unit. The linker regions between repeats are thus critical determinants of both spectrin's flexibility and polyfunctionality. The putative coupling of flexibility and ligand binding suggests a mechanism by which spectrin might participate in mechanosensory regulation.

SUBMITTER: Stabach PR

PROVIDER: S-EPMC2689040 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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The structure of the ankyrin-binding site of beta-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties.

Stabach Paul R PR Simonović Ivana I Ranieri Miranda A MA Aboodi Michael S MS Steitz Thomas A TA Simonović Miljan M Morrow Jon S JS

Blood 20090123 22

Spectrin and ankyrin participate in membrane organization, stability, signal transduction, and protein targeting; their interaction is critical for erythrocyte stability. Repeats 14 and 15 of betaI-spectrin are crucial for ankyrin recognition, yet the way spectrin binds ankyrin while preserving its repeat structure is unknown. We have solved the crystal structure of the betaI-spectrin 14,15 di-repeat unit to 2.1 A resolution and found 14 residues critical for ankyrin binding that map to the end ...[more]

PMID: 19168783

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Project description:BACKGROUND: Tandem repetition of structural motifs in proteins is frequently observed across all forms of life. Topology of repeating unit and its frequency of occurrence are associated to a wide range of structural and functional roles in diverse proteins, and defects in repeat proteins have been associated with a number of diseases. It is thus desirable to accurately identify specific repeat type and its copy number. Weak evolutionary constraints on repeat units and insertions/deletions between them make their identification difficult at the sequence level and structure based approaches are desired. The proposed graph spectral approach is based on protein structure represented as a graph for detecting one of the most frequently observed structural repeats, Ankyrin repeat. RESULTS: It has been shown in a large number of studies that 3-dimensional topology of a protein structure is well captured by a graph, making it possible to analyze a complex protein structure as a mathematical entity. In this study we show that eigen spectra profile of a protein structure graph exhibits a unique repetitive profile for contiguous repeating units enabling the detection of the repeat region and the repeat type. The proposed approach uses a non-redundant set of 58 Ankyrin proteins to define rules for the detection of Ankyrin repeat motifs. It is evaluated on a set of 370 proteins comprising 125 known Ankyrin proteins and remaining non-solenoid proteins and the prediction compared with UniProt annotation, sequence-based approach, RADAR, and structure-based approach, ConSole. To show the efficacy of the approach, we analyzed the complete PDB structural database and identified 641 previously unrecognized Ankyrin repeat proteins. We observe a unique eigen spectra profile for different repeat types and show that the method can be easily extended to detect other repeat types. It is implemented as a web server, AnkPred. It is freely available at 'bioinf.iiit.ac.in/AnkPred'. CONCLUSIONS: AnkPred provides an elegant and computationally efficient graph-based approach for detecting Ankyrin structural repeats in proteins. By analyzing the eigen spectra of the protein structure graph and secondary structure information, characteristic features of a known repeat family are identified. This method is especially useful in correctly identifying new members of a repeat family.

Project description:DNA tandem repeats, or satellites, are well described in eukaryotic species, but little is known about their prevalence across prokaryotes. Here, we performed the most complete characterization to date of satellites in bacteria. We identified 121,638 satellites from 12,233 fully sequenced and assembled bacterial genomes with a very uneven distribution. We also determined the families of satellites which have a related sequence. There are 85 genomes that are particularly satellite rich and contain several families of satellites of yet unknown function. Interestingly, we only found two main types of noncoding satellites, depending on their repeat sizes, 22/44 or 52 nucleotides (nt). An intriguing feature is the constant size of the repeats in the genomes of different species, whereas their sequences show no conservation. Individual species also have several families of satellites with the same repeat length and different sequences. This result is in marked contrast with previous findings in eukaryotes, where noncoding satellites of many sizes are found in any species investigated. We describe in greater detail these noncoding satellites in the spirochete Leptospira interrogans and in several bacilli. These satellites undoubtedly play a specific role in the species which have acquired them. We discuss the possibility that they represent binding sites for transcription factors not previously described or that they are involved in the stabilization of the nucleoid through interaction with proteins.IMPORTANCE We found an enigmatic group of noncoding satellites in 85 bacterial genomes with a constant repeat size but variable sequence. This pattern of DNA organization is unique and had not been previously described in bacteria. These findings strongly suggest that satellite size in some bacteria is under strong selective constraints and thus that satellites are very likely to play a fundamental role. We also provide a list and properties of all satellites in 12,233 genomes, which may be used for further genomic analysis.

Dataset Information

The structure of the ankyrin-binding site of beta-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties.

Publications

The structure of the ankyrin-binding site of beta-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties.

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