_________________________________________________________________________
We study how channels, transporters and receptors deliver
matter and information across biological membranes.
_________________________________________________________________________
At the Lee Lab, we are interested in molecular machines that perform membrane transport, broadly defined. We are especially interested in those that are involved in fundamental biological processes connected to disease. We are constantly engaged in applying and developing new approaches to gain deeper knowledge of the inner workings of these tiny devices.
Current Projects:
Polyamine Transporters
Polyamines are primordial organic polycations that occur in abundance in essentially all living creatures on this planet. The most famous polyamines are spermine, spermidine and putrescine, which exist as tetravalent (4+), trivalent (3+) and divalent (2+) cations under physiological conditions, respectively. Compared to other biologically important cations ions such as Na+, K+ and Ca2+, polyamines are enormous. These fascinating molecules bind nucleic acids and proteins to augment their shape, charge and behavior. This property endows polyamines with the ability to control a remarkably broad repertoire of fundamental processes necessary for cellular and organismal viability including gene regulation, translation, cell proliferation, electrical signaling and autophagy. Homeostatic transport and metabolic processes regulate the cellular polyamine pool. Understanding polyamine homeostasis is crucial because many human diseases are deeply connected to perturbations in polyamine abundance. While polyamine metabolism is well understood, the mechanism of polyamine transport across cell membranes has remained mysterious for decades. Remarkably, polyamine transport has been detected in virtually every organism studied. There are 18 known polyamine transporters in bacteria, fungi, trypanosomes and plants that are phylogenetically related to at least five structurally diverse transporter superfamilies. In metazoans, several solute carrier transporters and ATP-driven pumps are thought to transport polyamines. How do polyamine transporters recognize and select their polyamine cargo? How exactly do polyamine transporters shuttle polyamines across cell membranes? How are they distinguished from metal ion transporters? How is this molecular machinery controlled and regulated? How does their malfunction cause disease? How can we fix them when they break? These are the types of questions we pursue in this project. We have recently made significant inroads to elucidate the structure and mechanism of ATP13A2 (PARK9) — a lysosomal spermine-selective P5B family P-type adenosine triphosphatase (P5B-ATPase) linked to heritable neurodegenerative diseases associated with lysosomal dysfunction, most notably Parkinson’s disease (see here). Our work to more deeply understand ATP13A2’s mode of action and regulation is on-going.
Other Projects:
We are always developing new and exciting research ideas. Stay tuned for updates!