6kzj

Structural highlights

Disease

[ANK2_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]}

Function

[ANK2_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] [NDEL1_MOUSE] Required for organization of the cellular microtubule array and microtubule anchoring at the centrosome. May regulate microtubule organization at least in part by targeting the microtubule severing protein KATNA1 to the centrosome. Also positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus ends. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the centripetal motion of secretory vesicles and the coupling of the nucleus and centrosome. Also required during brain development for the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Plays a role, together with DISC1, in the regulation of neurite outgrowth. Required for mitosis in some cell types but appears to be dispensible for mitosis in cortical neuronal progenitors, which instead requires NDE1. Facilitates the polymerization of neurofilaments from the individual subunits NEFH and NEFL. Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (PubMed:27777970).^{[4] [5] [6] [7] [8] [9]}

References

1. ↑ Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, Song LS, Haurogne K, Kyndt F, Ali ME, Rogers TB, Lederer WJ, Escande D, Le Marec H, Bennett V. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003 Feb 6;421(6923):634-9. PMID:12571597 doi:10.1038/nature01335
2. ↑ Mohler PJ, Splawski I, Napolitano C, Bottelli G, Sharpe L, Timothy K, Priori SG, Keating MT, Bennett V. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9137-42. Epub 2004 Jun 3. PMID:15178757 doi:10.1073/pnas.0402546101
3. ↑ Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, Song LS, Haurogne K, Kyndt F, Ali ME, Rogers TB, Lederer WJ, Escande D, Le Marec H, Bennett V. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003 Feb 6;421(6923):634-9. PMID:12571597 doi:10.1038/nature01335
4. ↑ Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL, Ayala R, Tsai LH, Dobyns W, Ledbetter D, Hirotsune S, Wynshaw-Boris A. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet. 2003 Jul;34(3):274-85. PMID:12796778 doi:http://dx.doi.org/10.1038/ng1169
5. ↑ Nguyen MD, Shu T, Sanada K, Lariviere RC, Tseng HC, Park SK, Julien JP, Tsai LH. A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons. Nat Cell Biol. 2004 Jul;6(7):595-608. doi: 10.1038/ncb1139. Epub 2004 Jun 20. PMID:15208636 doi:http://dx.doi.org/10.1038/ncb1139
6. ↑ Shu T, Ayala R, Nguyen MD, Xie Z, Gleeson JG, Tsai LH. Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron. 2004 Oct 14;44(2):263-77. doi: 10.1016/j.neuron.2004.09.030. PMID:15473966 doi:http://dx.doi.org/10.1016/j.neuron.2004.09.030
7. ↑ Sasaki S, Mori D, Toyo-oka K, Chen A, Garrett-Beal L, Muramatsu M, Miyagawa S, Hiraiwa N, Yoshiki A, Wynshaw-Boris A, Hirotsune S. Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality. Mol Cell Biol. 2005 Sep;25(17):7812-27. doi: 10.1128/MCB.25.17.7812-7827.2005. PMID:16107726 doi:http://dx.doi.org/10.1128/MCB.25.17.7812-7827.2005
8. ↑ Toyo-Oka K, Sasaki S, Yano Y, Mori D, Kobayashi T, Toyoshima YY, Tokuoka SM, Ishii S, Shimizu T, Muramatsu M, Hiraiwa N, Yoshiki A, Wynshaw-Boris A, Hirotsune S. Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration. Hum Mol Genet. 2005 Nov 1;14(21):3113-28. Epub 2005 Oct 3. PMID:16203747 doi:http://dx.doi.org/ddi339
9. ↑ Fujiwara T, Ye S, Castro-Gomes T, Winchell CG, Andrews NW, Voth DE, Varughese KI, Mackintosh SG, Feng Y, Pavlos N, Nakamura T, Manolagas SC, Zhao H. PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. JCI Insight. 2016 Oct 20;1(17):e86330. doi: 10.1172/jci.insight.86330. PMID:27777970 doi:http://dx.doi.org/10.1172/jci.insight.86330
10. ↑ Ye J, Li J, Ye F, Zhang Y, Zhang M, Wang C. Mechanistic insights into the interactions of dynein regulator Ndel1 with neuronal ankyrins and implications in polarity maintenance. Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1207-1215. doi:, 10.1073/pnas.1916987117. Epub 2019 Dec 30. PMID:31889000 doi:http://dx.doi.org/10.1073/pnas.1916987117