The pendrin polypeptide

Abstract

Pendrin (SLC26A4) is an electroneutral anion exchanger in which functionaltering mutations cause inherited forms of non-syndromic (DFNB4) and syndromic deafness (Pendred syndrome) characterized by inner ear malformations. Elevated pendrin expression has also been identified as a risk modifier for inflammatory and infectious lung diseases. In addition, pharmacological inhibition of pendrin activity in the kidney is under development as a strategy for treatment of hypertension and diuretic-resistant fluid overload conditions. Although pendrin is an attractive therapeutic target for pharmaceutical development, the molecular structure and pharmacological inhibition profile of pendrin have remained elusive. Here, we present a new model of human pendrin structure based on the crystal structures of the transmembrane domain of the SLC26Dg fumarate transporter of Deinococcus geothermalis and of the cytosolic (carboxy terminal) STAS domain of rat prestin. The model proposes 14 membrane-spanning a-helices, with carboxy-terminal and amino-terminal regions located within the intracellular space. In addition, we summarize current knowledge on small-molecule modifiers of pendrin activity and on SLC26A4 gene sequence alterations encoding protein variants with modified functional and molecular features.