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Sanders Lab:

How Do Defects In Membrane Proteins Cause Disease?

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. The theme of our lab's work is to elucidate how defects in membrane proteins contribute to human diseases. 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 (including NMR). We are a biological problem-oriented lab. However, solving some of the problems we are interested in requires in-house development of new methods and technologies such as bicelles.

Specific Projects:
Peripheral Myelin Protein 22 and Charcot-Marie-Tooth Disease

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. Melanie Ohi, Bruce Carter, Jun Li, Carlos Vanoye, and Kevin Schey, all at Vanderbilt.

Potassium Channels and Heart Disease

We are examining the regulation of a human potassium channel involved in triggering heartbeat: KCNQ1. Mutations in this channels and the proteins that regulate it lead to heart disease. The Sanders lab is anchoring the structural end of collaborative studies of these proteins with the labs of Jens Meiler and Jarrod Smith (Vanderbilt), Carlos Vanoye and Al George (Northwestern), and Gary Lorigan (Miami U). We seek to understand how proteins such as KCNE1 are able to bind to and profoundly alter the channel properties of KCNQ1.

Amyloid Precursor Protein and Alzheimer's Disease

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). Collaborators on this project are Profs. Anne Kenworthy and Eric Hustedt of Vanderbilt, as well as Daniel Huster (U Leipzig, Germany), .


Integrins and Kidney Fibrosis

integrin activation

Kidney fibrosis is a common cause of death, particularly for patients with type 2 diabetes. Integrins are cell surface receptors that link the cell cytoskeleton to the extracellular matrix. We collaborate with Prof. Roy Zent, a Vanderbilt nephrologist, to elucidate key aspects of integrin biology and biophysics relevant to kidney health and disease. Our focus is on the roles of the integrin transmembrane domains in integrin structure and function, with a particular focus on the alpha1/beta1 and alpha2/beta1 collagen-specific integrins that are abundant in kidneys.