The SCHOOL of nature: I. Transmembrane signaling

Advances in Protein Chemistry and Structural Biology

2018

Intramembrane protein-protein interactions (PPIs) are involved in transmembrane signal transduction mediated by cell surface receptors and play an important role in health and disease. Recently, receptor-specific modulatory peptides rationally designed using a general platform of transmembrane signaling, the signaling chain homooligomerization (SCHOOL) model, have been proposed to therapeutically target these interactions in a variety of serious diseases with unmet needs including cancer, sepsis, arthritis, retinopathy, and thrombosis. These peptide drug candidates use ligand-independent mechanisms of action (SCHOOL mechanisms) and demonstrate potent efficacy in vitro and in vivo. Recent studies surprisingly revealed that in order to modify and/or escape the host immune response, human viruses use similar mechanisms and modulate cell surface receptors by targeting intramembrane PPIs in a ligand-independent manner. Here, I review these intriguing mechanistic similarities and discuss how the viral strategies optimized over a billion years of the coevolution of viruses and their hosts can help to revolutionize drug discovery science and develop new, disruptive therapies. Examples are given.

Section: Ppis In Transmembrane Signalingmentioning

confidence: 99%

Section: Single-chain Receptorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Targeting Intramembrane Protein–Protein Interactions: Novel Therapeutic Strategy of Millions Years Old

Advances in Protein Chemistry and Structural Biology

2018

Interplay Between Protein Order, Disorder and Oligomericity in Receptor Signaling

Advances in Experimental Medicine and Biology

2012

Receptor-mediated signaling plays an important role in health and disease. Recent reports have revealed that many proteins that do not adopt globular structures under native conditions, thus termed intrinsically disordered, are involved in cell signaling. Intriguingly, physiologically relevant oligomerization of intrinsically disordered proteins (IDPs) has been recently observed and shown to exhibit unique biophysical characteristics, including the lack of significant changes in chemical shift and peak intensity upon binding. On the other hand, ligand-induced or - tuned receptor oligomerization is known to be a general feature of various cell surface receptors and to play a crucial role in signal transduction. In this work, I summarize several distinct features of protein disorder that are especially important as related to signal transduction. I also hypothesize that interactions of IDPs with their protein or lipid partners represent a general biphasic process with the electrostatic-driven "no disorder-to-order" fast interaction which, depending on the interacting partner, may or may not be accompanied by the hydrophobic-driven slow formation of a secondary structure. Further, I suggest signaling-related functional connections between protein order, disorder and oligomericity and hypothesize that receptor oligomerization induced or tuned upon ligand binding outside the cell is translated across the membrane into protein oligomerization inside the cell, thus providing a general platform, the Signaling Chain HOmoOLigomerization (SCHOOL) platform, for receptor-mediated signaling. This structures our current multidisciplinary knowledge and views of the mechanisms governing the coupling of recognition to signal transduction and cell response. Importantly, this approach not only reveals previously unrecognized striking similarities in the basic mechanistic principles of function of numerous functionally diverse and unrelated surface membrane receptors, but also suggests the similarity between therapeutic targets, thus opening new horizons for both fundamental and clinically relevant studies.

Evolution of immunity: no development without risk

2011

Immunol Res

Signal transduction by cell surface receptors in the context of heterogeneous and variable cellular environments plays a pivotal role in regulating many biological processes, including development, activation, and homeostasis of the immune system. In some receptors, extracellular ligand-binding and intracellular signaling domains are located on the same protein chain (single-chain receptors), while in the so-called multichain immune recognition receptors (MIRRs), recognition and signaling functions are separated between different protein chains. Why did nature separate recognition and signaling functions for MIRRs, thereby increasing the risk of malfunction and potential attack by pathogens? The risk is real: in order to escape the immune response, viruses are able to disrupt functional coupling between recognition and signaling aspects of MIRR machinery. Intrinsic disorder of intracellular signal-generating regions of MIRRs adds further intrigue to the story. Why did nature select protein disorder for MIRRs to translate recognition of distinct antigens into appropriate activation signals that would induce specific functional outcomes? Here, I suggest that nature takes the risks associated with intrareceptor separation of functions as well as with the chaos and indeterminacy of protein disorder in exchange for providing diversity and variability of signal transduction. Not only does this phenomenon serve as the molecular basis for the development and evolution of the immune and other complex biological systems, but it fits closely to Darwinian evolutionary biology.