Phosphatidylinositol-4,5-Biphosphate (PIP(2)) Differentially Regulates the Interaction of Human Erythrocyte Protein 4.1 (4.1R) with Membrane Proteins.
Human erythrocyte protein 4.1 (4.1R) participates in organizing the plasma membrane by linking several surface-exposed transmembrane proteins to the internal cytoskeleton. In the present study, we characterized the interaction of 4.1R with phosphatidylinositol-4,5-bisphosphate (PIP(2)) and assessed the effect of PIP(2) on the interaction of 4.1R with membrane proteins. We found that 4.1R bound to PIP(2)-containing liposomes through its N-terminal 30 kDa membrane-binding domain and PIP(2) binding induced a conformational change in this domain. Phosphatidylinositol-4-phosphate (PIP) was a less effective inducer of this conformational change, and phosphatidylinositol (PI) and inositol-1,4,5-phosphate (IP(3)) induced no change. Replacement of amino acids K63,64 and K265,266 by alanine abolished the interaction of the membrane-binding domain with PIP(2). Importantly, binding of PIP(2) to 4.1R selectively modulated the ability of 4.1R to interact with its different binding partners. While PIP(2) significantly enhanced the binding of 4.1R to glycophorin C (GPC), it inhibited the binding of 4.1R to band 3 in vitro. PIP(2) had no effect on 4.1R binding to p55. Furthermore, GPC was more readily extracted by Titon X-100 from adenosine triphosphate (ATP)-depleted erythrocytes, implying that the GPC-4.1R interaction may be regulated by PIP(2) in situ. These findings define an important role for PIP(2) in regulating the function of 4.1R. Because 4.1R and its family members (4.1R, 4.1B, 4.1G, and 4.1N) are widely expressed and the PIP(2)-binding motifs are highly conserved, it is likely that the functions of other 4.1 proteins are similarly regulated by PIP(2) in many different cell types.[1]References
- Phosphatidylinositol-4,5-Biphosphate (PIP(2)) Differentially Regulates the Interaction of Human Erythrocyte Protein 4.1 (4.1R) with Membrane Proteins. An, X., Zhang, X., Debnath, G., Baines, A.J., Mohandas, N. Biochemistry (2006) [Pubmed]
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