4d8o | pdb_00004d8o
Crystal Structure of the ankyrin-B ZU5-ZU5-UPA-DD tandem
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 PubMedAnkyrin-R/B/G (encoded by ANK1/2/3, respectively) are a family of very large scaffold proteins capable of anchoring numerous receptors and ion channels to specific, spectrin-containing membrane micro-domains. Hereditary mutations of ankyrins are known to be associated with diseases including spherocytosis, cardiac arrhythmia, and bipolar disorder in humans, although the underlying molecular bases are poorly understood. The middle spectrin-binding domain of ankyrins contains highly conserved ZU5-ZU5-UPA-DD domains arranged into the ZZUD tandem. Curiously, most of the disease-causing mutations in the tandem have no apparent impact on the spectrin binding of ankyrins. The high resolution structure of the ankyrin-B ZZUD tandem determined here reveals that the ZU5-ZU5-UPA domains form a tightly packed structural supramodule, whereas DD is freely accessible. Although the formation of the ZZU supramodule does not influence the spectrin binding of ankyrins, mutations altering the interdomain interfaces of ZZU impair the functions of ankyrin-B&G. Our structural analysis further indicates that the ZZU supramodule of ankyrins has two additional surfaces that may bind to targets other than spectrin. Finally, the structure of the ankyrin ZZUD provides mechanistic explanations to many disease-causing mutations identified in ankyrin-B&R. Structure of the ZU5-ZU5-UPA-DD tandem of ankyrin-B reveals interaction surfaces necessary for ankyrin function.,Wang C, Yu C, Ye F, Wei Z, Zhang M Proc Natl Acad Sci U S A. 2012 Mar 12. PMID:22411828[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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