Novel linear motif filtering protocol reveals the role of the LC8 dynein light chain in the Hippo pathway.
Gábor ErdősTamás SzaniszlóMátyás PajkosBorbála Hajdu-SoltészBence KissGábor PálLászló NyitrayZsuzsanna DosztányiPublished in: PLoS computational biology (2017)
Protein-protein interactions (PPIs) formed between short linear motifs and globular domains play important roles in many regulatory and signaling processes but are highly underrepresented in current protein-protein interaction databases. These types of interactions are usually characterized by a specific binding motif that captures the key amino acids shared among the interaction partners. However, the computational proteome-level identification of interaction partners based on the known motif is hindered by the huge number of randomly occurring matches from which biologically relevant motif hits need to be extracted. In this work, we established a novel bioinformatic filtering protocol to efficiently explore interaction network of a hub protein. We introduced a novel measure that enabled the optimization of the elements and parameter settings of the pipeline which was built from multiple sequence-based prediction methods. In addition, data collected from PPI databases and evolutionary analyses were also incorporated to further increase the biological relevance of the identified motif hits. The approach was applied to the dynein light chain LC8, a ubiquitous eukaryotic hub protein that has been suggested to be involved in motor-related functions as well as promoting the dimerization of various proteins by recognizing linear motifs in its partners. From the list of putative binding motifs collected by our protocol, several novel peptides were experimentally verified to bind LC8. Altogether 71 potential new motif instances were identified. The expanded list of LC8 binding partners revealed the evolutionary plasticity of binding partners despite the highly conserved binding interface. In addition, it also highlighted a novel, conserved function of LC8 in the upstream regulation of the Hippo signaling pathway. Beyond the LC8 system, our work also provides general guidelines that can be applied to explore the interaction network of other linear motif binding proteins or protein domains.
Keyphrases
- protein protein
- amino acid
- simultaneous determination
- binding protein
- small molecule
- hiv testing
- randomized controlled trial
- mass spectrometry
- dna binding
- signaling pathway
- transcription factor
- liquid chromatography
- big data
- men who have sex with men
- network analysis
- solid phase extraction
- risk assessment
- epithelial mesenchymal transition
- cell proliferation
- climate change
- single cell
- induced apoptosis
- dna methylation
- high resolution
- bioinformatics analysis
- electronic health record
- neural network