Affinity and specificity of motif-based protein–protein interactions

Ivarsson, Ylva; Jemth, Per

doi:10.1016/j.sbi.2018.09.009

Cited by 105 publications

(97 citation statements)

References 81 publications

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“…Although the functional consequences of these combination SLiMs remain to be explored, simultaneous binding of both motifs to CN is unlikely, given the distance between LxVP and PxIxIT docking surfaces (Grigoriu et al, 2013). Instead, these SLiMs may mediate allovalent interactions where the presence of multiple pockets or motifs increases the probability of a re-binding event before the binding partners diffuse apart (Ivarsson and Jemth, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Because PSSM scoring and filtering steps were optimized for selectivity rather than sensitivity, it is likely that many proteins contain degenerate motifs that are functional, but relatively low scoring. In fact, multivalent SLiM-mediated interactions are often driven by a single high-affinity/consensus motif, known as a gatekeeper motif, in combination with degenerate variants of the motif that often diverge significantly from the classical consensus (Ivarsson and Jemth, 2018;Stevers et al, 2018;Yaffe, 2002).…”

Section: Computational Prediction and Validation Of Cn-binding Slimsmentioning

confidence: 99%

“…These interactions determine many critical properties of a protein including complex association, protein modification state, localization, and stability, and thereby control much of the decision making that directs a protein from translation to degradation (Van Roey et al, 2014). Recent discoveries show that SLiMs mediate specific interactions between protein phosphatases and their substrates (Brautigan and Shenolikar, 2018;Ivarsson and Jemth, 2018;Kataria et al, 2018). Systems-level elucidation of protein phosphatase signaling has been limited by technical challenges to substrate identification, but rapidly developing methods for SLiM discovery can now be harnessed to revolutionize our understanding of these enigmatic enzymes .…”

Section: Introductionmentioning

confidence: 99%

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Systematic discovery of Short Linear Motifs decodes calcineurin phosphatase signaling

Wigington

Roy

Damle

et al. 2019

Preprint

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Short linear motifs (SLiMs) form dynamic protein-protein interactions essential for signaling, but sequence degeneracy and low binding affinities make them difficult to identify. We harnessed unbiased systematic approaches for SLiM discovery to elucidate the regulatory network of calcineurin (CN), the Ca 2+ -regulated phosphatase that recognizes LxVP and PxIxIT motifs. In vitro proteome-wide detection of CN-binding peptides, in situ SLiM-dependent proximity labeling, and in silico modeling of motif determinants uncovered unanticipated CN interactors, including Notch1, which we establish as a CN substrate. Unexpectedly, CN shows SLiMdependent proximity to centrosomal and nuclear pore complex (NPC) proteins -structures where Ca 2+ signaling is largely uncharacterized. CN dephosphorylates human and yeast NPC proteins and promotes accumulation of a nuclear reporter, suggesting conserved NPC regulation by CN. The CN network assembled here provides a resource to investigate Ca 2+ and CN signaling and the demonstrated synergy between experimental and computational methods establishes a blueprint for examining SLiM-based networks.

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Section: Discussionmentioning

confidence: 99%

Section: Computational Prediction and Validation Of Cn-binding Slimsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Systematic discovery of Short Linear Motifs decodes calcineurin phosphatase signaling

Wigington

Roy

Damle

et al. 2019

Preprint

Self Cite

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“…However, it was recently demonstrated that SH3s can bind to 10 different categories of peptide motifs, including atypical Pro/Arg-less peptides (Teyra et al , 2017) . Modular domains such as SH3s are generally considered as acting as "beads on a string" by virtue of their ability to independently fold and bind to protein partners with high intrinsic specificity (Tong et al , 2002;Tonikian et al , 2009;Kay, 2012;Xin et al , 2013;Mayer, 2015;Kelil et al , 2017;Teyra et al , 2017;Ivarsson and Jemth, 2019;Cunningham et al , 2020) . Following this model, the large scale characterisation of the preferred binding motifs of individual S. cerevisiae , C. elegans and human SH3s has been performed systematically on isolated domains (Tong et al , 2002;Tonikian et al , 2009;Xin et al , 2013;Teyra et al , 2017) , either using peptide libraries in vitro or yeast two-hybrid assays (Y2H).…”

Section: Introductionmentioning

confidence: 99%

Protein context shapes the specificity of domain-peptide interactionsin vivo

Dionne

Bourgault

Dubé

et al. 2020

Preprint

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SRC Homology 3 (SH3) domains contribute to cellular processes via their ability to support protein-protein interactions (PPIs). While the intrinsic binding specificities of SH3 domains have been studied in vitro , whether each domain is necessary and sufficient to define PPI specificity in vivo is largely unknown. We combine genome editing, deep mutagenesis scanning, PPI mapping, growth phenotyping and single cell imaging in yeast to identify SH3-dependent PPI networks and their associated phenotypes. We show that both the sequence of the SH3 host protein and the position of the SH3 domains within their host are critical for interaction specificity and for cellular processes such as endocytosis. We further validate these findings using a human multi-SH3 adaptor protein and investigating its ability to promote phase separation. Our work highlights the importance of the interplay between a SH3 domain and its host protein for the regulation of cellular and biophysical processes.

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“…8 The affinity of such sites is often limited due to their small size, and hence multiple MoRFs are often combined into a multivalent interaction that are strengthened by avidity. 1,9 Avidity is thus crucial in the interactions of disordered proteins, but little work has addressed the role of the connecting linker in determining avidity. For multivalent MoRFs this connection can typically be expressed in terms of the length and physical characteristics of the sequence separating the binding sites.…”

Section: Introductionmentioning

confidence: 99%