Dataset Information

Structure of the ZU5-ZU5-UPA-DD tandem of ankyrin-B reveals interaction surfaces necessary for ankyrin function.

ABSTRACT: Ankyrin-R/B/G (encoded by ANK1/2/3, respectively) are a family of very large scaffold proteins capable of anchoring numerous receptors and ion channels to specific, spectrin-containing membrane micro-domains. Hereditary mutations of ankyrins are known to be associated with diseases including spherocytosis, cardiac arrhythmia, and bipolar disorder in humans, although the underlying molecular bases are poorly understood. The middle spectrin-binding domain of ankyrins contains highly conserved ZU5-ZU5-UPA-DD domains arranged into the ZZUD tandem. Curiously, most of the disease-causing mutations in the tandem have no apparent impact on the spectrin binding of ankyrins. The high resolution structure of the ankyrin-B ZZUD tandem determined here reveals that the ZU5-ZU5-UPA domains form a tightly packed structural supramodule, whereas DD is freely accessible. Although the formation of the ZZU supramodule does not influence the spectrin binding of ankyrins, mutations altering the interdomain interfaces of ZZU impair the functions of ankyrin-B&G. Our structural analysis further indicates that the ZZU supramodule of ankyrins has two additional surfaces that may bind to targets other than spectrin. Finally, the structure of the ankyrin ZZUD provides mechanistic explanations to many disease-causing mutations identified in ankyrin-B&R.

SUBMITTER: Wang C

PROVIDER: S-EPMC3323988 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Structure of the ZU5-ZU5-UPA-DD tandem of ankyrin-B reveals interaction surfaces necessary for ankyrin function.

Wang Chao C Yu Cong C Ye Fei F Wei Zhiyi Z Zhang Mingjie M

Proceedings of the National Academy of Sciences of the United States of America 20120312 13

Ankyrin-R/B/G (encoded by ANK1/2/3, respectively) are a family of very large scaffold proteins capable of anchoring numerous receptors and ion channels to specific, spectrin-containing membrane micro-domains. Hereditary mutations of ankyrins are known to be associated with diseases including spherocytosis, cardiac arrhythmia, and bipolar disorder in humans, although the underlying molecular bases are poorly understood. The middle spectrin-binding domain of ankyrins contains highly conserved ZU5- ...[more]

PMID: 22411828

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Project description:BackgroundTandem 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.ResultsIt 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'.ConclusionsAnkPred 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.

Dataset Information

Structure of the ZU5-ZU5-UPA-DD tandem of ankyrin-B reveals interaction surfaces necessary for ankyrin function.

Publications

Structure of the ZU5-ZU5-UPA-DD tandem of ankyrin-B reveals interaction surfaces necessary for ankyrin function.

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