Membrane proteins respresent a large and important class of membrane proteins that remain especially difficult to study. Over 60% of all drug molecules target membrane proteins. Moreover, hundreds of diseases involve the misassembly or misfolding of integral membrane proteins. The Sanders lab is devoted to characterizing the structures, folding and misfolding, and molecular mechanisms of membrane proteins using a variety of biochemical and biophysical methods (but especially NMR). We are a biological problem-oriented lab. However, some of the problems we wish to solve require in-house development of new methods and technologies such as bicelles.

Many diseases are linked to protein misfolding induced by mutations or other factors. Peripheral myelin protein 22 (PMP22) has four transmembrane segments and is a critical component of the myelin sheath surrounding the axons of the peripheral nervous system. Mutations in PMP22 that result in misfolding lead to Charcot-Marie-Tooth Disease, the most common inherited disorder of the peripheral nervous system. Studies of the structures, folding, stability, and molecular interactions of both wild type and disease-associated mutants of human PMP22 are being conducted in order to illuminate how mutations in this protein trigger misfolding and disease. Collaborators on this project include Profs. Bruce Carter, Jun Li, Carlos Vanoye, and Kevin Schey, all at Vanderbilt.

We are examining the regulation of the two human potassium channels that are involved in triggering heartbeat: HERG and KCNQ1. Mutations in these channels and the proteins that regulate them lead to heart disease. The Sanders lab is anchoring the structural end of collaborative studies of these proteins with the labs of Carlos Vanoye, Al George, Sabina Kupershmidt, Jarrod Smith, and Jens Meiler. We seek to understand how proteins such as KCNE1 are able to bind to and profoundly alter the channel properties of KCNQ1 and HERG.

The amyloid-beta polypeptides that are believed to trigger Alzheimer's disease are derived from the transmembrane amyloid precursor protein (APP). While much is known about the structural properties of the amyloid-beta polypeptides and the aggregates they form, much less is known about the structural biology of the competing pathways of APP cleavage that lead either to amyloid-beta formation or to non-amyloidogenic fragments. We are studying the structure of the critical transmembrane C99 domain of APP, its dimerization, and its interactions with a variety of molecules that are believed to be involved in modulating its cleavage, including cholesterol and GSAP (the gamma-secretase activating protein).

The human G protein-coupled receptor (GPCR) family has roughly 700 members and is the target of a sizable fraction of all current drugs. Our lab collaborates with several groups to study GPCRs and their interacting proteins: Profs. Rich Breyer (receptor pharmacology), Tina Iverson (X-ray crystallography), and Vsevold Gurevich (arrestin-receptor interactions). Current efforts focus on the complexes between GPCRs and the arrestins, with a focus on how receptors activate arrestins.