Cell surface receptors have important roles to play in the control of many cellular processes. They are activated when a ligand binds to an extracellular domain, which transmits a signal to an intracellular domain and then triggers a cascade of events inside the cell.
The human receptor tyrosine kinase (Met) and its ligand (hepatocyte growth factor) are essential during embryonic development and play an important role during cancer metastasis and tissue regeneration. The Met receptor is also relevant for infectious diseases and is the target of different bacteria, amongst them Listeria monocytogenes – one of the most virulent of food-borne pathogens that causes the infection listeriosis. However, despite much research, the actual process by which the Met receptor is activated was not completely understood. Mike Heilemann of the Goethe University Frankfurt and colleagues set out to investigate this problem in a comprehensive study published in BMC Biophysics.
Crystal structure of the MET receptor ectodomain (yellow, orange) in complex with the N terminal Met binding domain of bacterial ligand internalin B (purple, cyan), which is used by Listeria monocytogenes to infect host cells. Image source: Dietz et al, BMC Biophysics 2013, 6:6. Crystal structure data: RSCB PDB file 2UZY
For a receptor to become active, the ligand must bind to two domains. For most such receptors, these are thought to exist as separate individual monomers, in an inactive state – only becoming active once suitable ligands bind two domains together to form a dimer. However exceptions to this paradigm have been found, which exist as preformed dimers that still require conformational changes – induced by the binding of a ligand – to become active.
Clearly mechanisms of activation are variable among different receptors, so in a poorly-understood receptor such as Met, working out which states are operating presents a challenge. Do the domains exist as two inactive monomers, or are they present as single preformed dimers? Or, perhaps most intriguingly, could they exist as both?
Heilemann and colleagues attempt to answer this by using single-molecule fluorescence microscopy techniques to characterize the process of ligand-induced receptor dimerization. They provide direct evidence that the Met receptor does indeed exist as both monomers and dimers on the membrane of cells in the absence of the ligand, and that the proportion of Met dimers increases significantly upon ligand-binding. An accompanying commentary on the article by Xiaodong Pang and Huan-Xiang Zhou from Florida State University explains the significance of these findings and speculates on the form of receptor to which the ligand binds and whether such coexistence in multiple states may in fact be common for other cell surface receptors.