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Structural insights and ab initio sequencing within the DING proteins family.

ABSTRACT: DING proteins constitute an intriguing family of phosphate-binding proteins that was identified in a wide range of organisms, from prokaryotes and archae to eukaryotes. Despite their seemingly ubiquitous occurrence in eukaryotes, their encoding genes are missing from sequenced genomes. Such a lack has considerably hampered functional studies. In humans, these proteins have been related to several diseases, like atherosclerosis, kidney stones, inflammation processes and HIV inhibition. The human phosphate binding protein is a human representative of the DING family that was serendipitously discovered from human plasma. An original approach was developed to determine ab initio the complete and exact sequence of this 38 kDa protein by utilizing mass spectrometry and X-ray data in tandem. Taking advantage of this first complete eukaryotic DING sequence, a immunohistochemistry study was undertaken to check the presence of DING proteins in various mice tissues, revealing that these proteins are widely expressed. Finally, the structure of a bacterial representative from Pseudomonas fluorescens was solved at sub-angstrom resolution, allowing the molecular mechanism of the phosphate binding in these high-affinity proteins to be elucidated.

SUBMITTER: Elias M

PROVIDER: S-EPMC3004253 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Structural insights and ab initio sequencing within the DING proteins family.

Elias Mikael M Liebschner Dorothee D Gotthard Guillaume G Chabriere Eric E

Journal of synchrotron radiation 20101105 1

DING proteins constitute an intriguing family of phosphate-binding proteins that was identified in a wide range of organisms, from prokaryotes and archae to eukaryotes. Despite their seemingly ubiquitous occurrence in eukaryotes, their encoding genes are missing from sequenced genomes. Such a lack has considerably hampered functional studies. In humans, these proteins have been related to several diseases, like atherosclerosis, kidney stones, inflammation processes and HIV inhibition. The human ...[more]

PMID: 21169690

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Project description:BackgroundPredicting 3-dimensional protein structures from amino-acid sequences is an important unsolved problem in computational structural biology. The problem becomes relatively easier if close homologous proteins have been solved, as high-resolution models can be built by aligning target sequences to the solved homologous structures. However, for sequences without similar folds in the Protein Data Bank (PDB) library, the models have to be predicted from scratch. Progress in the ab initio structure modeling is slow. The aim of this study was to extend the TASSER (threading/assembly/refinement) method for the ab initio modeling and examine systemically its ability to fold small single-domain proteins.ResultsWe developed I-TASSER by iteratively implementing the TASSER method, which is used in the folding test of three benchmarks of small proteins. First, data on 16 small proteins (< 90 residues) were used to generate I-TASSER models, which had an average Calpha-root mean square deviation (RMSD) of 3.8A, with 6 of them having a Calpha-RMSD < 2.5A. The overall result was comparable with the all-atomic ROSETTA simulation, but the central processing unit (CPU) time by I-TASSER was much shorter (150 CPU days vs. 5 CPU hours). Second, data on 20 small proteins (< 120 residues) were used. I-TASSER folded four of them with a Calpha-RMSD < 2.5A. The average Calpha-RMSD of the I-TASSER models was 3.9A, whereas it was 5.9A using TOUCHSTONE-II software. Finally, 20 non-homologous small proteins (< 120 residues) were taken from the PDB library. An average Calpha-RMSD of 3.9A was obtained for the third benchmark, with seven cases having a Calpha-RMSD < 2.5A.ConclusionOur simulation results show that I-TASSER can consistently predict the correct folds and sometimes high-resolution models for small single-domain proteins. Compared with other ab initio modeling methods such as ROSETTA and TOUCHSTONE II, the average performance of I-TASSER is either much better or is similar within a lower computational time. These data, together with the significant performance of automated I-TASSER server (the Zhang-Server) in the 'free modeling' section of the recent Critical Assessment of Structure Prediction (CASP)7 experiment, demonstrate new progresses in automated ab initio model generation. The I-TASSER server is freely available for academic users http://zhang.bioinformatics.ku.edu/I-TASSER.

Dataset Information

Structural insights and ab initio sequencing within the DING proteins family.

Publications

Structural insights and ab initio sequencing within the DING proteins family.

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