Progress and prospects for structural studies of transmembrane interactions in single-spanning receptors

• Published in: Current opinion in structural biology 2016-08, Vol.39, p.115-123
• Main Authors: Trenker, Raphael, Call, Melissa J, Call, Matthew E
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Membrane - metabolism; Humans; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Protein Binding; Receptor Protein-Tyrosine Kinases - chemistry; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Cell Surface - metabolism
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2016.07.001

•Almost 50% of human membrane proteins are bitopic (single-spanning) proteins.•Transmembrane interactions guide the assembly and function of many bitopic cellular receptors.•New transmembrane structures inform on activation mechanisms for EGF receptor and other receptor tyrosine kinases.•Fas (CD95) transmembrane domains form trimeric structures that are required for Fas-mediated apoptosis induction.•Lipidic cubic phase crystallization opens the field to high-resolution X-ray structure determination. Single-spanning receptors are typically active in dimeric or oligomeric forms in which ligand-induced complex formation and/or conformational changes are the key events that transmit information across the cell membrane. This process is often depicted exclusively in terms of extracellular receptor–ligand interactions and their intracellular consequences, but the lipid-embedded α-helical transmembrane domains can also engage in specific intermolecular interactions that play important roles in establishing receptor complex structure and regulating signal propagation through the lipid bilayer. Obtaining high-resolution structural information on these interactions is extremely challenging, and the small number of structures currently available in the protein data bank represents only about a dozen unique receptors. In this review, we highlight new structures that provide novel insights into receptor tyrosine kinase and death receptor function and discuss the implications of recent successes in the application of X-ray crystallographic techniques to determine the structures of receptor transmembrane complexes in lipid bilayers.