Ankyrin protein networks in membrane formation and stabilization

Abstract

In eukaryotic cells, ankyrins serve as adaptor proteins that link membrane proteins to the underlying cytoskeleton. These adaptor proteins form protein complexes consisting of integral membrane proteins, signalling molecules and cytoskeletal components. With their modular architecture and ability to interact with many proteins, ankyrins organize and stabilize these protein networks, thereby establishing the infrastructure of membrane domains with specialized functions. To this end, ankyrin collaborates with a number of proteins including cytoskeletal proteins, cell adhesion molecules and large structural proteins. This review addresses the targeting and stabilization of protein networks related to ankyrin interactions with the cytoskeletal protein beta-spectrin, L1-cell adhesion molecules and the large myofibrillar protein obscurin. The significance of these interactions for differential targeting of cardiac proteins and neuronal membrane formation is also presented. Finally, this review concludes with a discussion about ankyrin dysfunction in human diseases such as haemolytic anaemia, cardiac arrhythmia and neurological disorders.

Figure 1

Ankyrin functional domains. The membrane binding domain consists of 24 ANK repeats that mediate interactions with a variety of ion channels, transporters and cell adhesion molecules. Ankyrin interacts with the cytoskeleton viaβ-spectrin binding to the spectrin binding domain. The death and C-terminal domains comprise the C-terminal regulatory domain that governs ankyrin inter- and intra-molecular interactions. NCX: sodium/calcium exchanger, NKA: sodium/potassium ATPase, IP³R: inositol_(1,4,5) triphosphate receptor.

Figure 2

Ankyrin-G targeting to membrane domains in the peripheral neuron. Ankyrin-G is recruited to the nodes of Ranvier by gliomedin, which is produced by Schwann cells and accumulates in the perinodal extracellular matrix. As a ligand for neurofascin-186, gliomedin causes the nodal clustering of this cell adhesion molecule, which in turn recruits to the nodal plasma membrane an ankyrin-G protein network consisting of voltage-gated sodium or potassium channels (KCNQ2/3) and β₄-spectrin. In contrast, ankyrin-G localization to the AIS is not dependent on an extracellular cue or neurofascin-186. The AIS targeting of ankyrin-G appears to be mediated by an intrinsic mechanism that has yet to be discovered, but AIS targeting of ankyrin-G associated proteins (i.e. neurofascin-186, sodium and potassium channels, β₄-spectrin) is dependent on ankyrin-G.

Figure 3

Ankyrin-B localization in ventricular cardiomyocytes. Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. Another population of ankyrin-B is located at the Z-lines where they interact with ion channels and transporters that regulate calcium efflux from the SR/T-tubule junction. The protein network associated with this ankyrin-B subpopulation includes NCX, NKA and the inositol_(1,4,5) triphosphate receptor (IP₃R).