Abstract
A cardiac hormone, atrial natriuretic peptide (ANP), plays a major role in blood pressure and volume regulation. ANP activities are mediated by a single span transmembrane receptor carrying intrinsic guanylate cyclase activity. ANP binding to its extracellular domain stimulates guanylate cyclase activity by an as yet unknown mechanism. Here we report the crystal structure of dimerized extracellular hormone-binding domain in complex with ANP. The structural comparison with the unliganded receptor reveals that hormone binding causes the two receptor monomers to undergo an intermolecular twist with little intramolecular conformational change. This motion produces a Ferris wheel-like translocation of two juxtamembrane domains in the dimer with essentially no change in the interdomain distance. This movement alters the relative orientation of the two domains by a shift equivalent to counterclockwise rotation of each by 24 degrees. These results suggest that transmembrane signaling by the ANP receptor is initiated via a hormone-induced rotation mechanism.
Highlights
From the ‡Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195 and the ʈAdvanced Photon Source, Argonne National Laboratory, Argonne, Illinois 60439
atrial natriuretic peptide (ANP) activities are mediated by a single span transmembrane receptor carrying intrinsic guanylate cyclase activity
The activities of ANP and B-type natriuretic peptide (BNP) are mediated by the ANP receptor or the A-type natriuretic peptide receptor carrying intrinsic guanylate cyclase (GCase) catalytic activity
Summary
Vol 279, No 27, Issue of July 2, pp. 28625–28631, 2004 Printed in U.S.A. Crystal Structure of Hormone-bound Atrial Natriuretic Peptide Receptor Extracellular Domain. The ANP receptor occurs as a dimer of a single span transmembrane polypeptide, each containing an extracellular hormone-binding domain and an intracellular domain consisting of a protein kinase-like, ATP-dependent regulatory domain and a GCase catalytic domain [7]. We have found that certain mutations at the headto-head dimer interface cause the receptor to become either uncoupled or constitutively GCase active, whereas mutations at the tail-to-tail dimer interface cause no such effect [21] These results strongly suggest that the extracellular domain of the native ANP receptor on the cell surface assumes the headto-head dimer structure and that the tail-to-tail apoANPR dimer previously described represents an artificial crystallographic dimer pair occurring only in the crystal packing. The comparison of the complex structure, occurring in the head-to-head configuration, with the unbound structure reveals a structural change caused by ANP binding and suggests a structural basis for transmembrane signaling by the ANP receptor
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