|Contact Information for College of Agriculture, Biotechnology & Natural Resources|
|Website||College of Agriculture, Biotechnology & Natural Resources|
|Location||Max Fleischmann Agriculture Building|
|Address||1664 N. Virginia Street
Reno, NV 89557-0222
We are interested in cell membrane receptors and their signal transduction mechanisms. Our current research focuses on the receptor for a cardiac hormone atrial natriuretic peptide (ANP) that plays a central role in blood pressure regulation and cardiovascular system maintenance and remodeling. The ANP receptor is a single-span transmembrane receptor carrying an intrinsic intracellular guanylate cyclase (GCase) catalytic activity. Binding of ANP to its extracellular domain stimulates GCase activity by an as yet unknown mechanism. The ANP receptor belongs to the super-family of single transmembrane receptors that include growth hormone receptors and cytokine receptors. Collectively, the signaling mechanism of these single transmembrane receptors is not known. Our research aims to determine the structure of ANP receptor at atomic resolution and to elucidate its signal transduction mechanism. We apply techniques of structural biology (X-ray crystallography), biochemistry, biophysics, and molecular biology to pursue our research goals.
Our current research focuses on the receptor for a cardiac hormone, atrial natriuretic peptide (ANP), which plays a major role in blood-pressure regulation by stimulating salt excretion and dilating arterial blood vessels. Aberrations in the ANP-ANP receptor system may lead to heart failure, hypertension, and other cardiovascular diseases. The ANP receptor occurs as a dimer of a type-I transmembrane protein which contains an extracellular hormone-binding domain and an intracellular domain consisting of an ATP-dependent regulatory domain and a GCase catalytic domain. ANP binding stimulates GCase catalysis by an as yet unknown mechanism. Our goal is to understand the mechanism of this transmembrane signaling by the ANP receptor. Toward this goal, we have expressed and purified the extracellular ANP-binding domain of the receptor (ANPR), and characterized its biochemical and biophysical properties. We have also determined the crystal structures of ANPR with and without bound ANP. Based on these structures and on the results of structure-guided mutagenesis, we have uncovered a novel structural mechanism, referred to as "rotation mechanism", for transmembrane signaling by the ANP receptor. We are pursuing these studies further with support from the NIH and American Heart Association.