Membrane receptor activation mechanisms and transmembrane peptide tools to elucidate them

Abstract

<jats:p>Single-pass membrane receptors contain extracellular domains that respond to external stimuli and transmit information to intracellular domains through a single transmembrane (TM) α-helix. Because membrane receptors have various roles in homeostasis, signaling malfunctions of these receptors can cause disease. Despite their importance, there is still much to be understood mechanistically about how single-pass receptors are activated. In general, single-pass receptors respond to extracellular stimuli via alterations in their oligomeric state. The details of this process are still the focus of intense study, and several lines of evidence indicate that the TM domain (TMD) of the receptor plays a central role. We discuss three major mechanistic hypotheses for receptor activation: ligand-induced dimerization, ligand-induced rotation, and receptor clustering. Recent observations suggest that receptors can use a combination of these activation mechanisms and that technical limitations can bias interpretation. Short peptides derived from receptor TMDs, which can be identified by screening or rationally developed on the basis of the structure or sequence of their targets, have provided critical insights into receptor function. Here, we explore recent evidence that, depending on the target receptor, TMD peptides cannot only inhibit but also activate target receptors and can accommodate novel, bifunctional designs. Furthermore, we call for more sharing of negative results to inform the TMD peptide field, which is rapidly transforming into a suite of unique tools with the potential for future therapeutics.</jats:p>

ASGR1 and Its Enigmatic Relative, CLEC10A

“…Activities of the receptors are also strongly affected by the extent of clustering induced by the ligand. Westerfield and Barrera [176] proposed a mechanism for receptor activation based on ligand-induced clustering that determines efficiency and sensitivity. At high receptor occupancy, the receptor may aggregate to a greater extent, which would exclude CD45, the ubiquitous protein tyrosine phosphatase on immune cells, and allow the phosphorylated receptors to prolong the initiation signal.…”

Transmembrane Peptides as Inhibitors of Protein-Protein Interactions: An Efficient Strategy to Target Cancer Cells?

“…Several studies have highlighted a major role for interactions between TM domains and their importance in membrane protein structure, function and assembly. Furthermore, mutations in these TM domains are often associated with numerous pathological contexts (5)(6)(7)(8)17). Although it was initially thought that the TM domain of RTKs as ErbB receptors was a passive anchor to the membrane, it is now well-established that it plays a key role in protein dimerization.…”

“…Activation of membrane receptors occurs most of the time by dimerization or oligomerization of these single-pass proteins in cell membranes and cumulative data underline the role of TM/TM domain interactions during the formation of these receptor complexes (5)(6)(7)(8). Nowadays, it is wellestablished that the TM domain plays a key role in receptor dimerization and activation (9).…”

Elucidation and refinement of synthetic receptor mechanisms

“…Although it is not clear why each substitution conferred these undesirable effects, it was clear that PCIL substitution alone did not address PC stability or background signaling via a useful mechanism, and so we turned to other modifications as alternative approaches. clustering (46). Therefore, we decided to investigate whether replacing the CD28-TMD in MESA with other TMD variants might improve receptor performance.…”

“…Given the promising results obtained with certain TMD choices, we next sought mechanistic insight into the roles of these domains in MESA signaling. For native receptors, TMDs can affect both localization and function (46), but how this choice affects synthetic receptor function is unexplored. Since some TMD sequence motifs mediate receptor homodimerization, we hypothesized that TMD choice might affect MESA receptor performance by modulating the propensity for chains to associate.…”