Discovery of short linear motif-mediated interactions through phage display of intrinsically disordered regions of the human proteome.

Journal article


Yadav, V. 2016. Discovery of short linear motif-mediated interactions through phage display of intrinsically disordered regions of the human proteome. The FEBS journal. Vol 284 (Issue 3), pp. 485-498. https://doi.org/10.1111/febs.13995
AuthorsYadav, V.
Abstract

The intrinsically disordered regions of eukaryotic proteomes are enriched in short linear motifs (SLiMs), which are of crucial relevance for cellular signaling and protein regulation; many mediate interactions by providing binding sites for peptide-binding domains. The vast majority of SLiMs remain to be discovered highlighting the need for experimental methods for their large-scale identification. We present a novel proteomic peptide phage display (ProP-PD) library that displays peptides representing the disordered regions of the human proteome, allowing direct large-scale interrogation of most potential binding SLiMs in the proteome. The performance of the ProP-PD library was validated through selections against SLiM-binding bait domains with distinct folds and binding preferences. The vast majority of identified binding peptides contained sequences that matched the known SLiM-binding specificities of the bait proteins. For SHANK1 PDZ, we establish a novel consensus TxF motif for its non-C-terminal ligands. The binding peptides mostly represented novel target proteins, however, several previously validated protein-protein interactions (PPIs) were also discovered. We determined the affinities between the VHS domain of GGA1 and three identified ligands to 40-130 μm through isothermal titration calorimetry, and confirmed interactions through coimmunoprecipitation using full-length proteins. Taken together, we outline a general pipeline for the design and construction of ProP-PD libraries and the analysis of ProP-PD-derived, SLiM-based PPIs. We demonstrated the methods potential to identify low affinity motif-mediated interactions for modular domains with distinct binding preferences. The approach is a highly useful complement to the current toolbox of methods for PPI discovery.

KeywordsShort Linear Motifs ; PPI; ProP-PD; Binding peptides
Year2016
JournalThe FEBS journal
Journal citationVol 284 (Issue 3), pp. 485-498
PublisherFEBS
Wiley Online Library
ISSN1742-4658
1742-464X
Digital Object Identifier (DOI)https://doi.org/10.1111/febs.13995
Web address (URL)https://doi.org/10.1111/febs.13995
https://pubmed.ncbi.nlm.nih.gov/28002650/
Output statusPublished
Publication dates
Online21 Dec 2016
18 Jan 2017
Online07 Feb 2017
Publication process dates
Accepted19 Dec 2016
Deposited15 Jun 2023
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