Ankyrins are a family of scaffold proteins, which serves to link great varieties of functional related but structurally diverse integral membrane proteins to the spectrin-based cytoskeletons. In vertebrates, the Ankyrin family consists of three members: ankyrin-R (AnkR), ankyrin-B (AnkB) and ankyrin-G (AnkG), encoded by ANK1, ANK2 and ANK3, respectively. Mutations in these genes have been linked to various human diseases, such as hemolytic anemia, ventricular arrhythmias and bipolar disorders. Ankyrin not only acts as a scaffold to organize the subcelluar domain structures, but also plays important roles in transporting membrane proteins, regulating their functions and controlling the cytoskeleton organization in these subcelluar regions. The molecular mechanisms of how ankyrin...[ Read more ]

Ankyrins are a family of scaffold proteins, which serves to link great varieties of functional related but structurally diverse integral membrane proteins to the spectrin-based cytoskeletons. In vertebrates, the Ankyrin family consists of three members: ankyrin-R (AnkR), ankyrin-B (AnkB) and ankyrin-G (AnkG), encoded by ANK1, ANK2 and ANK3, respectively. Mutations in these genes have been linked to various human diseases, such as hemolytic anemia, ventricular arrhythmias and bipolar disorders. Ankyrin not only acts as a scaffold to organize the subcelluar domain structures, but also plays important roles in transporting membrane proteins, regulating their functions and controlling the cytoskeleton organization in these subcelluar regions. The molecular mechanisms of how ankyrin regulate these processes remain mysterious. Different ankyrin isoforms have similar domain organizations. Moreover, the structured domains share very high sequence similarities among different ankyrin across different isoforms and species. However, AnkR, AnkB and AnkG usually localize to different subcelluar regions and perform divergent and non-redundant functions. The molecular mechanisms underlying such isoform specificities are still poorly understood.

An ankyrin-B-specific linker region was reported to prevent AnkB from associating with plasma membranes by autoinhibiting its membrane binding domain (MBD), whereas ankyrin-G do not have this sequence so that it could localize to the plasma membrane region. However my study found that not only ankyrin-B but also ankyrin-G possesses the linker-mediated autoinhibition, both with high affinities but with different amino acid sequences. To gain insight into the detailed molecular interactions, the crystal structures of the linker-ankyrin repeats auto-inhibiting complexes of ankyrin-B were solved and multiple binding sites were identified. Through comprehensive biochemical assays, I demonstrated that the ankyrin-B’s and ankyrin-G’s linkers bind to the MBD by adopt different binding site-combinations and they could block the membrane targets in some binding sites of the MBD. This may imply a potential regulating strategy for ankyrin-membrane targets interactions.