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4.1 Proteins: Ion Transporters in Check

Wataru Nunomura, Hideki Wakui, Yuichi Takakuwa and Philippe Gascard

The classical function of 4.1R in erythrocytes is to contribute to the mechanical properties of the membrane by promoting the interaction between spectrin and actin. It is now well recognized that 4.1R is required for the stable anchorage of numerous cell surface erythrocyte membrane proteins. 4.1R is the prototypical member of the family of 4.1 proteins, which are expressed in many cell types, besides erythrocytes. The other members of the protein 4.1 family include 4.1N, 4.1G, and 4.1B.NHE1 (Na+/H+ exchanger isoform 1) has been reported to be hyperactive in 4.1R-null erythrocytes, supporting a functional interaction between NHE1 and 4.1R. We recently demonstrated that 4.1R binds directly to the cytoplasmic domain of NHE1 (NHE1cd). This interaction involves an EED motif in the 4.1R FERM (4.1/ezrin/radixin/moesin) domain and two clusters of basic amino acids in the NHE1cd, K519R and R556FNKKYVKK, previously shown to mediate PIP2 (phosphatidylinositol 4,5-bisphosphate) binding. The affinity of this interaction is reduced in hypertonic and acidic conditions, demonstrating that this interaction is of electrostatic nature. The binding affinity is also reduced upon binding of Ca2+/CaM (Ca2+-saturated calmodulin) to the 4.1R FERM domain. We propose that 4.1R regulates NHE1 activity, through a direct protein-protein interaction that can be modulated by intracellular pH, as well as Na+ and Ca2+ concentrations. In this review, we discuss the increasing evidence for an important role for members of the protein 4.1 family of membrane skeletal proteins, in the regulation of various ion transporters in erythrocytes and in non-erythroid cells.