SHEPHARD: a modular and extensible software architecture for analyzing and annotating large protein datasets

Ginell, Garrett M.; Flynn, Aidan J; Holehouse, Alex S.

doi:10.1101/2022.09.18.508433

Cited by 6 publications

(7 citation statements)

References 44 publications

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“…The protein sequence analysis was conducted using SHEPHARD, a Python-based framework designed for integrating and analyzing large-scale amino acid sequence properties 124 . IDRs were predicted and annotated using metapredict (V2) 125 .…”

Section: Methodsmentioning

confidence: 99%

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Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease

Boeynaems

Rosa

Yeong

et al. 2023

Preprint

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Positively charged repeat peptides are emerging as key players in neurodegenerative diseases. These peptides can perturb diverse cellular pathways but a unifying framework for how such promiscuous toxicity arises has remained elusive. We used mass-spectrometry-based proteomics to define the protein targets of these neurotoxic peptides and found that they all share similar sequence features that drive their aberrant condensation with these positively charged peptides. We trained a machine learning algorithm to detect such sequence features and unexpectedly discovered that this mode of toxicity is not limited to human repeat expansion disorders but has evolved countless times across the tree of life in the form of cationic antimicrobial and venom peptides. We demonstrate that an excess in positive charge is necessary and sufficient for this killer activity, which we name polycation poisoning. These findings reveal an ancient and conserved mechanism and inform ways to leverage its design rules for new generations of bioactive peptides.

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Section: Methodsmentioning

confidence: 99%

“…Protein abundance analyses (Fig. S7–11) were performed using SHEPHARD 124 and sparrow (https://github.com/idptools/sparrow). Mass spectrometry data were obtained for humans 128 , X. laevis 129 , A. thaliana 130 , E. coli 131 , S. pombe 132 , and S. cerevisiae 133 .…”

Section: Methodsmentioning

confidence: 99%

Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease

Boeynaems

Rosa

Yeong

et al. 2023

Preprint

Self Cite

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“…To this end, we calculated all homotypic ɛ values for all human IDRs that possess one or more phosphosite (19,703 IDRs) before and after making phosphomimetic mutations. Only experimentally-reported phosphosites (S/T/Y) were used, and in all cases, were converted to E (glutamic acid) ( 67 , 68 ). Interestingly, ∼57% of IDRs that undergo phosphorylation showed a reduction in homotypic attractive interaction upon phosphorylation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Rational sequence designs used for examining homopolymer vs. IDR properties were generated using GOOSE ( 124 ). Proteome-wide analysis was performed using SHEPHARD, with data obtained from UniProt ( 67 , 125 ). We make extensive use of previously published experimental data and are indebted to the authors for their previously published careful biophysical and biochemical studies.…”

Section: Methodsmentioning

confidence: 99%

Direct prediction of intermolecular interactions driven by disordered regions

Ginell,

Emenecker,

Lotthammer

et al. 2024

Preprint

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Intrinsically disordered regions (IDRs) are critical for a wide variety of cellular functions, many of which involve interactions with partner proteins. Molecular recognition is typically considered through the lens of sequence-specific binding events. However, a growing body of work has shown that IDRs often interact with partners in a manner that does not depend on the precise order of the amino acid order, instead driven by complementary chemical interactions leading to disordered bound-state complexes. Despite this emerging paradigm, we lack tools to describe, quantify, predict, and interpret these types of structurally heterogeneous interactions from the underlying amino acid sequences. Here, we repurpose the chemical physics developed originally for molecular simulations to develop an approach for predicting intermolecular interactions between IDRs and partner proteins. Our approach enables the direct prediction of phase diagrams, the identification of chemically-specific interaction hotspots on IDRs, and a route to develop and test mechanistic hypotheses regarding IDR function in the context of molecular recognition. We use our approach to examine a range of systems and questions to highlight its versatility and applicability.

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“…Proteome-wide bioinformatics was performed using SPARROW (https://github.com/idptools/sparrow) and SHEPHARD 66 . SPARROW is an in-development Python package for calculating IDR sequence properties, while SHEPHARD is a hierarchical analysis framework for annotating and analyzing large sets of protein sequences.…”

Section: Bioinformaticsmentioning

confidence: 99%

Direct prediction of intrinsically disordered protein conformational properties from sequence

Lotthammer,

Ginell,

Griffith

et al. 2024

Biophysical Journal

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SHEPHARD: a modular and extensible software architecture for analyzing and annotating large protein datasets

Cited by 6 publications

References 44 publications

Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease

Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease

Direct prediction of intermolecular interactions driven by disordered regions

Direct prediction of intrinsically disordered protein conformational properties from sequence

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