With special project funding from UKRO, Dr. Alexander Pushkin from the Division of Nephrology at UCLA has been investigating the structure and function of a transporter protein, with the long-term goal of developing treatments for acid-based disorders such as renal tubular acidosis.
Using transmission electron microscopy, Dr. Pushkin has succeeded in generating a three-dimensional (3D) low-resolution model of erythrocyte anion exchanger 1 (AE1), a sodium-bicarbonate transporter present in the red blood cell membrane. AE1 is mutated in kidney and blood diseases, and knowledge of its 3D organization will help scientists understand the mechanisms behind these disorders. Numerous previous efforts to solve the structure of AE1 using X-ray crystallography, transmission electron microscopy, and other methods have failed. In this study using single-particle electron microscopy, Dr. Pushkin has obtained the first 3D structure of full-length AE1 at 2.4 nm resolution. The experiment revealed a surprising characteristic feature of full-length AE1; the domains of the cytoplasm and cell membrane are connected by a flexible linker. Pushkin proposes that this unique structural feature of the AE1 connector region is involved in the flexibility of red blood shape. The importance of this mechanism for kidney function is currently under investigation.