Organizational model of human erythrocyte band 3 (anion-exchange protein). The protein contains 2 structurally and functionally distinct domains: a cytoplasmic binding domain (amino acids 1-359) and a transmembrane domain (amino acids 360-911) that forms the anion-exchange channel.78 In the cytoplasmic domain, the glycolytic enzymes PFK, aldolase, and G3PD bind to amino acids 1 to 23 at the N-terminus of band 3 and contact amino acids 356 to 384,79 which are nearby in the folded protein. The enzymes are inactive when bound,80 but are displaced and activated by deoxyhemoglobin (Hb), which also binds to the N-terminus,81 or by phosphorylation of 2 tyrosines (Tyr21-P and Tyr8-P) within the binding sites.80 Enolase, PK and LDH also localize to the membrane and are displaced by deoxyhemoglobin, but do not bind to band 3.80 This fact suggests that many of the enzymes in the glycolytic pathway form a functional complex (or “metabolon”) that efficiently generates adenosine triphosphate (ATP), particularly under hypoxic conditions. Ankyrin also interacts with the N-terminus,82 but the main ankyrin sites are amino acids 63-73 and 175-185, which loop out from the surface.71 Protein 4.1 binds to 2 sites with the (I/L)RRRY motif, near the end of the domain.83 Ankyrin and protein 4.1R inhibit each other’s binding. The binding sites for protein 4.2 and adducin have not been identified. In the membrane domain, the best current model84 for the anion-exchange channel is based on the structure of the ClC bacterial chloride channel. The intramembrane and transmembrane helices are lettered as they are in the ClC channel. A complex carbohydrate structure is attached to Asn 642. Carbonic anhydrase (CA)IV binds to the extracellular loop of band 3 between helices I and J,85 and CAII may bind to the C-terminal segment86 ; both are perfectly positioned to create bicarbonate from carbon dioxide and to shuttle the ions to or from the plasma through band 3. F-6-P, fructose 6-phosphate; Hb-O2, oxyhemoglobin; NAc, acetylated aminoterminus.
