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Kunio Misono
Adjunct Professor

Contact Information

  • Email: kmisono@unr.edu
  • Phone: (775) 784-4690
    Lab (775-327-2251
  • Fax: (775) 784-1419
  • Office: Howard Medical Sciences 151
  • Mail Stop: 330

Degrees

  • Saitama University, Japan, 1969
  • University of Osaka Pref., Japan, 1971
  • Vanderbilt University, 1978

Research Interests

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.

Selected Publications

  • Misono KS, Ogawa H, Qiu Y, and Ogata CM. Structural studies of the natriuretic peptide receptor: a novel hormone-induced rotation mechanism for transmembrane signal transduction (review). Peptides, in press (2005).
  • Ogawa H, Qiu Y, Ogata C and Misono KS. Crystal structure of hormone-bound atrial natriuretic peptide receptor extracellular domain: Rotation mechanism for transmembrane signal transduction. J Biol Chem 279: 28625-31, 2004.
  • Qiu Y, Ogawa H, Zhang X and Misono KS. Constitutive activation and uncoupling of the atrial natriuretic peptide receptor by mutations at the dimerization interface: Role of dimer structure in transmembrane signaling. J Biol Chem 279: 6115-6123. 2004.
  • Ogawa H, Zhang X, Qiu Y, Ogata C and Misono KS. Crystallization and X-ray analysis of Atrial Natriuretic Peptide (ANP) receptor extracellular domain complexed with ANP: Use of ammonium sulfate as cryoprotectant. Acta Crystallography, D59, 1831-3, 2003.
  • Misono KS. Natriuretic peptide receptor: structure and signaling (review). Mol Cell Biochem, 230: 49-60, 2002.
  • Misono KS. Atrial natriuretic factor binding to its receptor is dependent on chloride concentration: A possible feedback-control mechanism in renal salt regulation. Circ Res 86:1135-1139, 2000.
  • van den Akker F, Zhang X, Miyagi M, Huo X, Misono KS*, and Yee VC* Structure of the dimerized hormone binding domain of a guanylyl cyclase-coupled receptor. Nature 406:101-104, 2000.
  • Miyagi M, Zhang, X, and Misono KS. Identification and characterization of glycosylation sites in the extracellular domain of the atrial natriuretic peptide receptor: Oligosaccharide structures are not required for hormone binding. Eur J Biochem. 267:5758-5768, 2000.
  • Miyagi M, and Misono KS. Disulfide bond structure of the atrial natriuretic peptide receptor extracellular domain: conserved disulfide bonds among guanylate cyclase-coupled receptors. Biochimica et Biophysica Acta 1478:30-38, 2000.
  • Misono, K. S., Sivasubramanian, N., Berkner, K. and Zhang, X. Expression and purification of the extracellular ligand-binding domain of the atrial natriuretic peptide receptor. Biochemistry, 38: 516-523, 1999.
  • Huo X, Abe T, and Misono KS. Ligand-binding induced limited proteolysis of the atrial natriuretic peptide receptor: proline-rich hinge structure critical for transmembrane signal transduction. Biochemistry 38:16941-6951, 1999.

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