Understanding single‐pass transmembrane receptor signaling from a structural viewpoint—what are we missing?

Abstract

Single‐pass transmembrane receptors are involved in essential processes of both physiological and pathological nature and represent more than 1300 proteins in the human genome. Despite the high biological relevance of these receptors, the mechanisms of the signal transductions they facilitate are incompletely understood. One major obstacle is the lack of structures of the transmembrane domains that connect the extracellular ligand‐binding domains to the intracellular signaling platforms. Over a period of almost 20 years since the first structure was reported, only 21 of these receptors have become represented by a transmembrane domain structure. This scarceness stands in strong contrast to the significance of these transmembrane α‐helices for receptor functionality. In this review, we explore the properties and qualities of the current set of structures, as well as the methodological difficulties associated with their characterization and the challenges left to be overcome. Without an increased and focused effort to bring this class of proteins on par with the remaining membrane protein field, a serious lag in their biological understanding looms. Design of pharmaceutical agents, prediction of mutational affects in relation to disease, and deciphering of functional mechanisms require high‐resolution structural information, especially when dealing with a domain carrying so much functionality in so few residues.

Transmembrane Signal Transduction in Two‐Component Systems: Piston, Scissoring, or Helical Rotation?

“…Consequently, only the four remaining relative motions can occur: Moving toward or away from each other (which amounts to association or dissociation); moving perpendicular to the membrane plane (piston‐like motions); pivoting (also called scissoring or tilting); and finally rotation (gearbox‐like) . We note that the question of TM signaling by single pass proteins is widely discussed in the context of eukaryotic proteins, such as receptor tyrosine kinases …”

“…[77,78] We note that the question of TM signaling by single pass proteins is widely discussed in the context of eukaryotic proteins, such as receptor tyrosine kinases. [79][80][81][82] In dimeric double-pass receptors, presence of additional transmembrane helices further restricts the motions available to individual helices. At the same time, because the number of the helices is increased, the number of the collective motions is also increased.…”

A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer

“…Therefore, the liquid order of a particular membrane microdomain might have an impact on the orientation behavior of membrane proteins, as shown here [50]. It has been reported that the NMR structure of an isolated TLR3-TM domain in dodecylphosphocholine micelles exists as a right-handed dimer with a helix-crossing angle of -51.1 • [51]. The substantial tilt and curvature and the consistent crossing angle of TM helices in our simulations indicate that the hydrophobic mismatch shapes the TM domain organization of full-length TLR3 in the cell membrane [52].…”

Membrane Orientation and Oligomerization of the Melanocortin Receptor Accessory Protein 2

“…Currently, there is very little information regarding MRAP2 structure and it is not uncommon for single-pass transmembrane proteins to have intrinsically disordered domains making them difficult to study using classic biophysical techniques 30 . These disordered regions often have functional importance since this flexibility allows them to interact with multiple protein partners.…”