Intrinsic Disorder in Transmembrane Proteins: Roles in Signaling and Topology Prediction

Abstract

Intrinsically disordered regions (IDRs) are peculiar stretches of amino acids that lack stable conformations in solution. Intrinsic Disorder containing Proteins (IDP) are defined by the presence of at least one large IDR and have been linked to multiple cellular processes including cell signaling, DNA binding and cancer. Here we used computational analyses and publicly available databases to deepen insight into the prevalence and function of IDRs specifically in transmembrane proteins, which are somewhat neglected in most studies. We found that 50% of transmembrane proteins have at least one IDR of 30 amino acids or more. Interestingly, these domains preferentially localize to the cytoplasmic side especially of multi-pass transmembrane proteins, suggesting that disorder prediction could increase the confidence of topology prediction algorithms. This was supported by the successful prediction of the topology of the uncharacterized multi-pass transmembrane protein TMEM117, as confirmed experimentally. Pathway analysis indicated that IDPs are enriched in cell projection and axons and appear to play an important role in cell adhesion, signaling and ion binding. In addition, we found that IDP are enriched in phosphorylation sites, a crucial post translational modification in signal transduction, when compared to fully ordered proteins and to be implicated in more protein-protein interaction events. Accordingly, IDPs were highly enriched in short protein binding regions called Molecular Recognition Features (MoRFs). Altogether our analyses strongly support the notion that the transmembrane IDPs act as hubs in cellular signal events.

Diacylglycerol Acyltransferase 1 Is Regulated by Its N-Terminal Domain in Response to Allosteric Effectors

“…The presence of IDRs is common in higher organisms. Indeed, a recent study found that IDRs are found in 50% of membrane proteins and usually are localized at the cytoplasmic face of the lipid bilayer (Bürgi et al, 2016). Computational studies also showed that multipass membrane proteins tend to have longer (;70 residues) IDRs facing the cytosol (Bürgi et al, 2016).…”

“…Indeed, a recent study found that IDRs are found in 50% of membrane proteins and usually are localized at the cytoplasmic face of the lipid bilayer (Bürgi et al, 2016). Computational studies also showed that multipass membrane proteins tend to have longer (;70 residues) IDRs facing the cytosol (Bürgi et al, 2016). This agrees with previous studies of plant DGAT1 indicating that the N-terminal region resides on the cytosolic face of the ER (Shockey et al, 2006;Weselake et al, 2006).…”

Presence and structure‐activity relationship of intrinsically disordered regions across mucins

“…16 However, it is now well established that intrinsically disordered proteins (IDPs) and regions (IDRs) are complete proteins (or segments of proteins) that lack a traditional globular secondary or tertiary structure, yet are fully functional. [17][18][19][20][21][22] Disordered regions generally are sequences of low complexity with a low proportion of hydrophobic residues and a high number of repeating residues with a preponderance of polar and charged residues. 23,24 This lack of bulky hydrophobic amino acids prevents the formation of an ordered core that comprises a traditional structured domain.…”

The Un(f)told Story of General Anesthesia

“…In relation to the extra‐ and intracellular aqueous phases, volatile anesthetics achieve much higher concentrations in biomembranes (10–100 m m ), where they are accumulated preferentially at the membrane/water interface . Neurotransmitter release requires the fusion of synaptic vesicles to the presynaptic membrane, which is especially rich in disordered proteins . A pivotal step of this process is the self‐assembly of the so‐called ternary SNARE complex composed of three neuronal membrane proteins, including syntaxin, SNAP‐25, and synaptobrevin.…”

“…ID sequences and domains are abundant not only in cytosolic proteins but also in membrane proteins and are involved in the regulation of crucial cellular signaling pathways . Computational data analysis has indicated that 40–50 % of human plasma membrane proteins possess ID regions of 30 or more consecutive residues localized preferentially on the cytoplasmic side …”