Structural basis underlying strong interactions between ankyrins and spectrins

Author:

Li Jianchao,Chen Keyu,Zhu Ruichi,Zhang MingjieORCID

Abstract

AbstractAnkyrins (encoded byANK1/2/3corresponding to Ankyrin-R/B/G or AnkR/B/G), via binding to spectrins, connect plasma membranes with actin cytoskeleton to maintain mechanical strengths and to modulate excitabilities of diverse cells such as neurons, muscle cells, and erythrocytes. Cellular and genetic evidences suggest that each isoform of ankyrins pairs with a specific β-spectrin in discrete subcellular membrane microdomains for distinct functions, though the molecular mechanisms underlying such ankyrin/β-spectrin pairings are unknown. In this study, we discover that a conserved and short extension N-terminal to the ZU5N-ZU5C-UPA tandem (exZZU) is critical for each ankyrin to bind to β-spectrins with high affinities. Structures of AnkB/G exZZU in complex with spectrin repeats13-15 of β2/β4-spectrins solved here reveal that the extension sequence of exZZU forms an additional β-strand contributing to the structural stability and enhanced affinity of each ZU5N/spectrin repeat interaction. The junction site between the extension and ZU5Nis exactly the position of a splicing-mediated miniexon insertion site of AnkB/G. The complex structures further reveal that the UPA domain of exZZU directly participates in spectrin binding. Formation of the exZZU supramodule juxtaposes the ZU5Nand UPA domains for simultaneous interacting with spectrin repeats 14 and 15. However, our biochemical and structural investigations indicate that the direct and strong interactions between ankyrins and β-spectrins do not appear to determine their pairing specificities. Therefore, there likely exists additional mechanism(s) for modulating functional pairings between ankyrins and β-spectrins in cells.

Publisher

Cold Spring Harbor Laboratory

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