Di-/tri- and especially tetrapeptides incorporating the sequence DADD present in the carboxyterminal region of the bicarbonate/chloride anion exchanger AE1 strongly activate human carbonic anhydrase (CA) isozyme II, whereas they act as more inefficient activators of isozymes I and IV. This discovery suggests that in the metabolon hCA II-AE1, the last protein plays a role both as a CA activator as well as a bicarbonate transporter. A synthesis of the tripeptide DAD and the tetrapeptide DADD is also presented together with the possible explanation why such highly acidic oligopeptides efficiently bind to hCA II but not to the closely related isozymes I and IV.