Abstract Transmembrane receptors are the major mediators of signaling for cells to communicate with the environment, playing essential roles in many cellular processes, including migration, proliferation and immunity. Malfunction of these receptors are associated with diseases such as cancer and neurological disorders. The long-term goal of this research program is to understand the general mechanisms by which signal is transduced from one to the other side of the membrane through the transmembrane region of receptors, in particular single-pass transmembrane receptors. On the other hand, each receptor has its own unique properties and mechanisms. We also study the individual characteristic features of these receptors, especially larger assemblies beyond the ligand-induced dimeric receptor paradigm. A better understanding of the transmembrane signaling mechanisms of these receptors will lay the foundation for the development of targeted therapies for associated diseases. We use structural approaches, including both cryo-EM and X-ray crystallography, in combination with in vitro biophysical and biochemical analyses and cell-based functional assays. In the past, we had focused mostly on plexin, the largest family of guidance receptors critical for the development of the nervous and cardiovascular systems. Plexin activated by the semaphorin ligand transduces repulsive signal to steer the growth cone of the neuron for the formation of the neuronal network. Plexin is also critical for regulating immunity and wound healing. In the next few years, one major goal of the work on plexin is to understand how the transmembrane regions of plexin and its co-receptor neuropilin couple the extracellular ligand-binding region and the intracellular effector region for precise controlling of signaling across the plasma membrane. In particular, we will analyze novel regulatory mechanisms endowed by large assemblies of semaphorin, plexin and neuropilin. In addition, we will expand our work to other receptors involved in the neuronal, cardiovascular and immune systems. For example, neuropilin also serves as a co- receptor for VEGF receptor (VEGFR), a receptor tyrosine kinase essential for vasculogenesis and angiogenesis. Neuropilin can dramatically increases the potency of VEGF in activating VEGFR. We will analyze the mechanism of the signaling enhancing effect of neuropilin on VEGFR. The functions of semaphorin also extent beyond plexin. Red blood cell-derived Sema7A binds GPIb, a protein complex specifically expressed on platelets, and thereby stimulates thrombo-inflammation in myocardial ischemia- reperfusion injury. GPIb contains transmembrane receptors GPIbα, GPIbβ and GPIX in a 1:2:1 stoichiometry. The best-known function of GPIb is triggering platelet activation in response to VWF (von WilleBrand Factor), vital to hemostasis. We will analyze how Sema7A and VWF bind GPIb and how the binding induces the activation of GPIb.