Phosphorylation of Annexin A1 by TRPM7 Kinase: A Switch Regulating the Induction of an α-Helix

TRPM7 is an unusual bifunctional protein consisting of an a-kinase domain fused to a TRP ion channel. Previously, we have identified annexin A1 as a substrate for TRPM7 kinase and found that TRPM7 phosphorylates annexin A1 at Ser5 within the N-terminal alpha-helix. Annexin A1 is a Ca2+-dependent membrane binding protein, which has been implicated in membrane trafficking and reorganization. The N-terminal tail of annexin Al can interact with either membranes or S100A11 protein, and it adopts the conformation of an amphipathic a-helix upon these interactions. Moreover, the existing evidence indicates that the formation of an alpha-helix is essential for these interactions. Here we show that phosphorylation at Ser5 prevents the N-terminal peptide of annexin A1 from adopting an alpha-helical conformation in the presence of membrane-mimetic micelles as well as phospholipid vesicles. We also show that phosphorylation at Ser5 dramatically weakens the binding of the peptide to S100A11. Our data suggest that phosphorylation at Ser5 regulates the interaction of annexin A1 with membranes as well as S100A11 protein.