Protein Disorder and Short Conserved Motifs in Disordered Regions Are Enriched near the Cytoplasmic Side of Single-Pass Transmembrane Proteins

Abstract

Intracellular juxtamembrane regions of transmembrane proteins play pivotal roles in cell signalling, mediated by protein-protein interactions. Disordered protein regions, and short conserved motifs within them, are emerging as key determinants of many such interactions. Here, we investigated whether disorder and conserved motifs are enriched in the juxtamembrane area of human single-pass transmembrane proteins. Conserved motifs were defined as short disordered regions that were much more conserved than the adjacent disordered residues. Human single-pass proteins had higher mean disorder in their cytoplasmic segments than their extracellular parts. Some, but not all, of this effect reflected the shorter length of the cytoplasmic tail. A peak of cytoplasmic disorder was seen at around 30 residues from the membrane. We noted a significant increase in the incidence of conserved motifs within the disordered regions at the same location, even after correcting for the extent of disorder. We conclude that elevated disorder within the cytoplasmic tail of many transmembrane proteins is likely to be associated with enrichment for signalling interactions mediated by conserved short motifs.

Hydrogen-exchange mass spectrometry for the study of intrinsic disorder in proteins

“…Determination of structures of receptor cytoplasmic tails is difficult as they are usually small, have several disordered regions, and are subject to post translational modifications and conformational changes upon ligand binding 46 . HXMS can be extremely useful in determining folded and unfolded regions of cytoplasmic tails of receptors.…”

Cadherin juxtamembrane region derived peptides inhibit TGFβ1 induced gene expression

“… 6 - 12 In a previous in silico analysis we showed that disordered regions tend to reside in the juxtamembrane region of transmembrane proteins potentially accommodating linear motifs. 13 A family of transmembrane proteins, cadherins, was predicted to contain potential bioactive regions close to the membrane at their cytoplasmic side. Cadherins mediate Ca 2+ -dependent, homophillic, cell-cell interactions, called adherens junctions.…”

Putative linear motifs mediate the trafficking to apical and basolateral membranes

“…Dozens of pieces of evidence are required to confirm the functionality of a linear motif, as the information content of the peptide is very low and most of their occurrence in proteins are just 'random' false positive hits. There are several other efforts for the large scale computational identification and analysis of putative linear motifs in membrane proteins [35]. Here we demonstrated that such considerations have a strong predictive power, even if a significant proportion of the identified motifs is likely not functional.…”