Protein promiscuity and its implications for biotechnology

Nobeli, Irene; Favia, Angelo D.; Thornton, Janet M.

doi:10.1038/nbt1519

Cited by 456 publications

(402 citation statements)

References 117 publications

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“…[3][4][5] Previous studies have suggested structural flexibility through large disordered regions, [6][7][8][9] and distributed surface charge, especially in small hubs (less than 300 residues) with no disordered regions. 9,10 The presence of multiple domains in hubs has also been suggested, 11,12 the reasoning being that multiple domains correspond to multiple interaction interfaces 13 and greater functional complexity. 14 Indeed, several hubs have multiple domains containing several binding sites.…”

Section: Introductionmentioning

confidence: 99%

Domain distribution and intrinsic disorder in hubs in the human protein–protein interaction network

2010

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Intrinsic disorder and distributed surface charge have been previously identified as some of the characteristics that differentiate hubs (proteins with a large number of interactions) from non-hubs in protein-protein interaction networks. In this study, we investigated the differences in the quantity, diversity, and functional nature of Pfam domains, and their relationship with intrinsic disorder, in hubs and non-hubs. We found that proteins with a more diverse domain composition were over-represented in hubs when compared with non-hubs, with the number of interactions in hubs increasing with domain diversity. Conversely, the fraction of intrinsic disorder in hubs decreased with increasing number of ordered domains. The difference in the levels of disorder was more prominent in hubs and non-hubs with fewer domains. Functional analysis showed that hubs were enriched in kinase and adaptor domains acting primarily in signal transduction and transcription regulation, whereas non-hubs had more DNA-binding domains and were involved in catalytic activity. Consistent with the differences in the functional nature of their domains, hubs with two or more domains were more likely to connect distinct functional modules in the interaction network when compared with single domain hubs. We conclude that the availability of greater number and diversity of ordered domains, in addition to the tendency to have promiscuous domains, differentiates hubs from non-hubs and provides an additional means of achieving interaction promiscuity. Further, hubs with fewer domains use greater levels of intrinsic disorder to facilitate interaction promiscuity with the prevalence of disorder decreasing with increasing number of ordered domains.

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Section: Introductionmentioning

confidence: 99%

Domain distribution and intrinsic disorder in hubs in the human protein–protein interaction network

2010

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“…Enzymes are commonly viewed as highly specific for their natural substrates; however, this view obscures the fact that many have the ability to perform multiple activities (1,2). This "promiscuity" typically involves the same chemistry applied to different substrates or, alternatively, can use different catalytic machinery within the same active site (3,4).…”

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confidence: 99%

Tracing Determinants of Dual Substrate Specificity in Glycoside Hydrolase Family 5

Chen

Friedland

Pereira

et al. 2012

Journal of Biological Chemistry

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Background: Glycoside hydrolase family 5 (GH5) comprises enzymes with a wide range of activities critical for the deconstruction of lignocellulose. Results: Concurrent glucan and mannan specificity in over 70 members of GH5 can be ascribed to a conserved active site motif. Conclusion: Single domain multispecific hydrolases are widely prevalent. Significance: This finding has potential applications in improved enzyme mixture design or microbes engineered for consolidated bioprocessing of lignocellulose.

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“…5 The gold standard to identify these residues remains systematic mutational analysis, [6][7][8] but this approach has some high throughput limitations. Inadequate choice and availability of assays reduce sensitivity while the promiscuity of binding 9 or catalysis, 10 as well as poor reproducibility of the relevant cellular context, 11 reduce specificity.…”

Section: Introductionmentioning

confidence: 99%

Sequence and structure continuity of evolutionary importance improves protein functional site discovery and annotation

et al. 2010

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Protein functional sites control most biological processes and are important targets for drug design and protein engineering. To characterize them, the evolutionary trace (ET) ranks the relative importance of residues according to their evolutionary variations. Generally, top-ranked residues cluster spatially to define evolutionary hotspots that predict functional sites in structures. Here, various functions that measure the physical continuity of ET ranks among neighboring residues in the structure, or in the sequence, are shown to inform sequence selection and to improve functional site resolution. This is shown first, in 110 proteins, for which the overlap between top-ranked residues and actual functional sites rose by 8% in significance. Then, on a structural proteomic scale, optimized ET led to better 3D structure-function motifs (3D templates) and, in turn, to enzyme function prediction by the Evolutionary Trace Annotation (ETA) method with better sensitivity of (40% to 53%) and positive predictive value (93% to 94%). This suggests that the similarity of evolutionary importance among neighboring residues in the sequence and in the structure is a universal feature of protein evolution. In practice, this yields a tool for optimizing sequence selections for comparative analysis and, via ET, for better predictions of functional site and function. This should prove useful for the efficient mutational redesign of protein function and for pharmaceutical targeting.

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Protein promiscuity and its implications for biotechnology

Cited by 456 publications

References 117 publications

Domain distribution and intrinsic disorder in hubs in the human protein–protein interaction network

Domain distribution and intrinsic disorder in hubs in the human protein–protein interaction network

Tracing Determinants of Dual Substrate Specificity in Glycoside Hydrolase Family 5

Sequence and structure continuity of evolutionary importance improves protein functional site discovery and annotation

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