Abstract
Conformational protein properties are coupled to protein functionality and could provide a useful parameter for functional annotation of differentially expressed genes in transcriptome studies. The aim was to determine whether predicted intrinsic protein disorder was differentially associated with proteins encoded by genes that are differentially regulated in lymphoma cells upon interaction with stromal cells, an interaction that occurs in microenvironments, such as lymph nodes that are protective for lymphoma cells during chemotherapy. Intrinsic disorder protein properties were extracted from the Database of Disordered Protein Prediction (D2P2), which contains data from nine intrinsic disorder predictors. Proteins encoded by differentially regulated cell-adhesion regulated genes were enriched in intrinsically disordered regions (IDRs) compared to other genes both with regard to IDR number and length. The enrichment was further ascribed to down-regulated genes. Consistently, a higher proportion of proteins encoded by down-regulated genes contained at least one IDR or were completely disordered. We conclude that down-regulated genes in stromal cell-adherent lymphoma cells encode proteins that are characterized by elevated levels of intrinsically disordered conformation, indicating the importance of down-regulating functional mechanisms associated with intrinsically disordered proteins in these cells. Further, the approach provides a generally applicable and complementary alternative to classification of differentially regulated genes using gene ontology or pathway enrichment analysis.
Highlights
Genome-wide approaches to identify genes that are differentially expressed under different conditions of interest have become a standard approach to investigating mechanisms involved in biological processes
To determine whether there might be a difference in the frequency of intrinsically disordered regions (IDRs) in proteins encoded by adhesion-regulated genes compared to other proteins, we calculated the percentage of IDRs in adhesion-related proteins for each IDR predictor (Figure 1, blue line) and compared it to the proportion of genes in the adhesion-regulated gene set (5.4%, Figure 1, red line)
The main finding of this work is that proteins encoded by genes that are down-regulated in lymphoma cells upon adhering to stromal cells, typically found in microenvironments that increase cancer-cell survival, tend to have more frequent and longer regions of predicted intrinsically disordered conformation than proteins encoded by up-regulated genes or other expressed genes in the same cells
Summary
Genome-wide approaches to identify genes that are differentially expressed under different conditions of interest have become a standard approach to investigating mechanisms involved in biological processes. The analysis pipeline used in such studies generally leads quickly to some form of gene ontology analysis, in order to identify biological functions that are associated with the differentially regulated genes. Characterisation of differentially regulated genes in relation to predicted or known conformational properties of the proteins they encode would be of interest in the light of recent discoveries showing overall relationships between conformational properties and different types of protein functionality or mechanism of action [1]. The catalytic domains of enzymes are generally ordered globular conformations while transcription factors are characterised by a preponderance of intrinsic disorder leading to ensembles of many alternative conformational forms [2]. It is clear that about half the proteins in eukaryotes contain at least one extended (>30 amino acid residues) intrinsically disordered region (IDR) and some proteins are completely disordered [3]
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