A Functional Map of the Human Intrinsically Disordered Proteome

Pritišanac, Iva; Alderson, T. Reid; Kolarić, Đesika; Zarin, Taraneh; Xie, Shuting; Lu, Alex; Alam, Aqsa; Maqsood, Abdullah; Youn, Ji-Young; Forman-Kay, Julie D.; Moses, Alan M.

doi:10.1101/2024.03.15.585291

Cited by 7 publications

(1 citation statement)

References 192 publications

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“…The C-terminal regions of proteins have been extensively studied in eukaryotic cells 51,52 , where 'short linear motifs' within intrinsically disordered regions 53 have been associated with a broad spectrum of functions, including substrate recognition 51,54 , signaling 55 , and disease risk 51,56 .…”

Section: Chimeric Defluorinases Indicate Importance Of the C-terminal...mentioning

confidence: 99%

Enzymatic carbon-fluorine bond cleavage by human gut microbes

Probst,

Felder,

Poltorak

et al. 2024

Preprint

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The human gut microbiota is known for its pharmaceutical biotransformation capabilities. Many pharmaceuticals are fluorinated; however, it was previously unknown whether gut microbes were capable of cleaving carbon-fluorine bonds. Here we show that dehalogenases encoded by human gut microbes, including Clostridia, Bacilli, and Coriobacteriia, are active on fluorinated amino and organic acids. Through the development of a rapid, 96-well fluoride detection assay, we screened and characterized new microbial gut defluorinases. Using alanine scanning and chimeric protein design, we identified a 41 amino acid carboxyl-terminal region which is necessary and sufficient to enable defluorination activity when fused to a non-defluorinating dehalogenase. Based on this carboxyl-terminal region alone, we were able to predict the defluorination or non-defluorination activity of microbial dehalogenases with >83% accuracy. By uncovering the hidden potential of human gut microbes to catalyze defluorination reactions, our findings lay the foundation for therapeutic interventions relevant to human and gut microbiome health.

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Section: Chimeric Defluorinases Indicate Importance Of the C-terminal...mentioning

confidence: 99%

Enzymatic carbon-fluorine bond cleavage by human gut microbes

Probst,

Felder,

Poltorak

et al. 2024

Preprint

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SHARK enables sensitive detection of evolutionary homologs and functional analogs in unalignable and disordered sequences

Chow,

Ghosh,

Hadarovich

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered regions (IDRs) are structurally flexible protein segments with regulatory functions in multiple contexts, such as in the assembly of biomolecular condensates. Since IDRs undergo more rapid evolution than ordered regions, identifying homology of such poorly conserved regions remains challenging for state-of-the-art alignment-based methods that rely on position-specific conservation of residues. Thus, systematic functional annotation and evolutionary analysis of IDRs have been limited, despite them comprising ~21% of proteins. To accurately assess homology between unalignable sequences, we developed an alignment-free sequence comparison algorithm, SHARK (Similarity/Homology Assessment by Relating K-mers). We trained SHARK-dive, a machine learning homology classifier, which achieved superior performance to standard alignment-based approaches in assessing evolutionary homology in unalignable sequences. Furthermore, it correctly identified dissimilar but functionally analogous IDRs in IDR-replacement experiments reported in the literature, whereas alignment-based tools were incapable of detecting such functional relationships. SHARK-dive not only predicts functionally similar IDRs at a proteome-wide scale but also identifies cryptic sequence properties and motifs that drive remote homology and analogy, thereby providing interpretable and experimentally verifiable hypotheses of the sequence determinants that underlie such relationships. SHARK-dive acts as an alternative to alignment to facilitate systematic analysis and functional annotation of the unalignable protein universe.

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Sequence- and chemical specificity define the functional landscape of intrinsically disordered regions

Langstein-Skora¹,

Schmid²,

Emenecker

et al. 2022

Preprint

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Intrinsically disordered protein regions (IDRs) pervasively engage in essential molecular functions, yet they are often poorly conserved as assessed by sequence alignment. To understand the seeming paradox of how sequence variability is compatible with function, we examined the functional determinants for a poorly conserved but essential IDR. We show that IDR function depends on two distinct but related properties: sequence- and chemical specificity. While sequence-specificity works via linear binding motifs, chemical-specificity reflects the sequence-encoded chemistry of multivalent interactions through amino acids across an IDR. Unexpectedly, an apparently essential binding motif can be removed if compensatory changes to the sequence chemistry are made, highlighting the orthogonality and interoperability of both properties. Our results provide a general framework to understand the functional constraints on IDR sequence evolution.

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A Functional Map of the Human Intrinsically Disordered Proteome

Cited by 7 publications

References 192 publications

Enzymatic carbon-fluorine bond cleavage by human gut microbes

Enzymatic carbon-fluorine bond cleavage by human gut microbes

SHARK enables sensitive detection of evolutionary homologs and functional analogs in unalignable and disordered sequences

Sequence- and chemical specificity define the functional landscape of intrinsically disordered regions

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