6m3q | pdb_00006m3q
Crystal structure of AnkB/beta4-spectrin complex
Structural highlights
DiseaseANK2_HUMAN Romano-Ward syndrome. Long QT syndrome 4 (LQT4) [MIM:600919: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. Long QT syndrome type 4 shows many atypical features compared to classical long QT syndromes, including pronounced sinus bradycardia, polyphasic T waves and atrial fibrillation. Cardiac repolarization defects may be not as severe as in classical LQT syndromes and prolonged QT interval on EKG is not a consistent feature. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] FunctionANK2_HUMAN In skeletal muscle, required for proper localization of DMD and DCTN4 and for the formation and/or stability of a special subset of microtubules associated with costameres and neuromuscular junctions (By similarity). Attaches integral membrane proteins to cytoskeletal elements. Also binds to cytoskeletal proteins. Required for coordinate assembly of Na/Ca exchanger, Na/K ATPase and InsP3 receptor at sarcoplasmic reticulum sites in cardiomyocytes. Required for the coordinated expression of the Na/K ATPase, Na/Ca exchanger and beta-2-spectrin (SPTBN1) in the inner segment of rod photoreceptors. Required for expression and targeting of SPTBN1 in neonatal cardiomyocytes and for the regulation of neonatal cardiomyocyte contraction rate.[3] Publication Abstract from PubMedAnkyrins (encoded by ANK1/2/3 corresponding 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 beta-spectrin in discrete subcellular membrane microdomains for distinct functions, though the molecular mechanisms underlying such ankyrin/beta-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 beta-spectrins with high affinities. Structures of AnkB/G exZZU in complex with spectrin repeats13-15 of beta2/beta4-spectrins solved here reveal that the extension sequence of exZZU forms an additional beta-strand contributing to the structural stability and enhanced affinity of each ZU5N/spectrin repeat interaction. The complex structures further reveal that the UPA domain of exZZU directly participates in spectrin binding. Formation of the exZZU supramodule juxtaposes the ZU5N and 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 beta-spectrins do not appear to determine their pairing specificities. Therefore, there likely exists additional mechanism(s) for modulating functional pairings between ankyrins and beta-spectrins in cells. Structural Basis Underlying Strong Interactions between Ankyrins and Spectrins.,Li J, Chen K, Zhu R, Zhang M J Mol Biol. 2020 Apr 27. pii: S0022-2836(20)30321-1. doi:, 10.1016/j.jmb.2020.04.023. PMID:32353364[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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