Structural Biology outside the box — inside the cell

Plitzko, Jürgen M.; Schuler, Benjamin; Selenko, Philipp

doi:10.1016/j.sbi.2017.06.007

Cited by 82 publications

(72 citation statements)

References 102 publications

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“…These large-scale quantitative annotations will help understand the biological role of order and disorder, and serve as a basis to construct predictive models. As NMR measurements of proteins in their native complex environments, such as inside living cells, are becoming more common ( 59 ), we will be able to address fundamental biological questions with greater physiological relevance ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

MobiDB 3.0: more annotations for intrinsic disorder, conformational diversity and interactions in proteins

Piovesan

Tabaro

Paladin

et al. 2017

Nucleic Acids Research

202

164

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The MobiDB (URL: mobidb.bio.unipd.it) database of protein disorder and mobility annotations has been significantly updated and upgraded since its last major renewal in 2014. Several curated datasets for intrinsic disorder and folding upon binding have been integrated from specialized databases. The indirect evidence has also been expanded to better capture information available in the PDB, such as high temperature residues in X-ray structures and overall conformational diversity. Novel nuclear magnetic resonance chemical shift data provides an additional experimental information layer on conformational dynamics. Predictions have been expanded to provide new types of annotation on backbone rigidity, secondary structure preference and disordered binding regions. MobiDB 3.0 contains information for the complete UniProt protein set and synchronization has been improved by covering all UniParc sequences. An advanced search function allows the creation of a wide array of custom-made datasets for download and further analysis. A large amount of information and cross-links to more specialized databases are intended to make MobiDB the central resource for the scientific community working on protein intrinsic disorder and mobility.

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Section: Discussionmentioning

confidence: 99%

MobiDB 3.0: more annotations for intrinsic disorder, conformational diversity and interactions in proteins

Piovesan

Tabaro

Paladin

et al. 2017

Nucleic Acids Research

202

164

View full text Add to dashboard Cite

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“…As they are involved in essentially all major human diseases, they also represent promising novel targets for drug discovery 4,5 . Experimental methods to characterize IDPs and IDRs include X-ray crystallography, nuclear magnetic resonance spectroscopy (NMR), small-angle X-ray scattering (SAXS), circular dichroism (CD) and Förster resonance energy transfer (FRET) [6][7][8][9] . Each technique provides a unique point of view on the phenomenon of intrinsic disorder (ID) and multiple experimental evidence gives researchers insights over the functioning mechanisms of IDPs.…”

Section: Introductionmentioning

confidence: 99%

Critical Assessment of Protein Intrinsic Disorder Prediction

Necci

Piovesan

Predictors

et al. 2020

Preprint

136

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Intrinsically disordered proteins defying the traditional protein structure-function paradigm represent a challenge to study experimentally. As a large part of our knowledge rests on computational predictions, it is crucial for their accuracy to be high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in predicting intrinsically disordered regions in proteins and the subset of disordered residues involved in binding other molecules. A total of 43 methods, 32 for disorder and 11 for binding regions, were evaluated on a dataset of 646 proteins. The best methods use modern machine learning techniques and significantly outperform widely used first-generation methods across different types of targets. Disordered binding regions remain hard to predict correctly, which offers significant potential for improvement. Intriguingly, some of the top performing methods are also among the fastest.

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“…CCS acts as a metallochaperone through its N-terminal Atx1-like domain (D1) and as oxidoreductase through its C-terminal domain (D3), whereas the second, SOD-like domain (D2) is responsible for the interaction with SOD1 15 – 24 . Recently, the maturation steps of SOD1 have been observed in living human cells 25 through in-cell NMR 26 , 27 . It has been shown that some WT-L fALS SOD1 mutants fail to bind zinc when they are overexpressed in the human cytoplasm, and accumulate as unstructured species that may act as precursors in the pathogenic aggregation pathway 28 .…”

Section: Introductionmentioning

confidence: 99%

A molecular chaperone activity of CCS restores the maturation of SOD1 fALS mutants

Luchinat

Barbieri

Banci

2017

Sci Rep

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Superoxide dismutase 1 (SOD1) is an important metalloprotein for cellular oxidative stress defence, that is mutated in familiar variants of Amyotrophic Lateral Sclerosis (fALS). Some mutations destabilize the apo protein, leading to the formation of misfolded, toxic species. The Copper Chaperone for SOD1 (CCS) transiently interacts with SOD1 and promotes its correct maturation by transferring copper and catalyzing disulfide bond formation. By in vitro and in-cell NMR, we investigated the role of the SOD-like domain of CCS (CCS-D2). We showed that CCS-D2 forms a stable complex with zinc-bound SOD1 in human cells, that has a twofold stabilizing effect: it both prevents the accumulation of unstructured mutant SOD1 and promotes zinc binding. We further showed that CCS-D2 interacts with apo-SOD1 in vitro, suggesting that in cells CCS stabilizes mutant apo-SOD1 prior to zinc binding. Such molecular chaperone function of CCS-D2 is novel and its implications in SOD-linked fALS deserve further investigation.

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Structural Biology outside the box — inside the cell

Cited by 82 publications

References 102 publications

MobiDB 3.0: more annotations for intrinsic disorder, conformational diversity and interactions in proteins

MobiDB 3.0: more annotations for intrinsic disorder, conformational diversity and interactions in proteins

Critical Assessment of Protein Intrinsic Disorder Prediction

A molecular chaperone activity of CCS restores the maturation of SOD1 fALS mutants

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