title: The Metamorphic Nature of the Tau Protein: Dynamic Flexibility Comes at a Cost.
abstract: Accumulation of the microtubule associated protein tau occurs in several neurodegenerative diseases including Alzheimer's disease (AD). The tau protein is intrinsically disordered, giving it unique structural properties that can be dynamically altered by post-translational modifications such as phosphorylation and cleavage. Over the last decade, technological advances in nuclear magnetic resonance (NMR) spectroscopy and structural modeling have permitted more in-depth insights into the nature of tau. These studies have helped elucidate how metamorphism of tau makes it ideally suited for dynamic microtubule regulation, but how it also facilitates tau self-assembly, oligomerization, and neurotoxicity. This review will focus on how the distinct structure of tau governs its function, accumulation, and toxicity as well as how other cellular factors such as molecular chaperones control these processes.
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida Tampa, FL, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Sabbagh
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida Tampa, FL, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
keywords: NMR; microtubules; neurodegenerative diseases; structure; tau
references.citation: ACS Chem Biol. 2012 Oct 19;7(10):1677-86
references.pmid: 22769591
references.citation: Acta Neuropathol. 2002 Jan;103(1):26-35
references.pmid: 11837744
references.citation: Biochemistry. 2008 Jul 15;47(28):7393-404
references.pmid: 18558718
references.citation: J Biol Chem. 2004 Feb 6;279(6):4869-76
references.pmid: 14612456
references.citation: Mol Biol Cell. 1997 Feb;8(2):353-65
references.pmid: 9190213
references.citation: J Clin Invest. 2004 Jul;114(1):121-30
references.pmid: 15232619
references.citation: Biochemistry. 2009 Oct 27;48(42):10047-55
references.pmid: 19769346
references.citation: J Neurochem. 2006 May;97(4):1005-14
references.pmid: 16606369
references.citation: J Biol Chem. 2006 Dec 22;281(51):39413-23
references.pmid: 17056594
references.citation: Structure. 2015 Aug 4;23(8):1448-58
references.pmid: 26165593
references.citation: Nat Med. 2015 Oct;21(10):1154-62
references.pmid: 26390242
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7737-41
references.pmid: 9636220
references.citation: J Am Chem Soc. 2011 Oct 12;133(40):15842-5
references.pmid: 21910444
references.citation: Proteins. 2012 Feb;80(2):454-62
references.pmid: 22072628
references.citation: Biochem Soc Trans. 2010 Aug;38(4):1016-20
references.pmid: 20658996
references.citation: J Neurosci. 2009 Sep 30;29(39):12079-88
references.pmid: 19793966
references.citation: Curr Alzheimer Res. 2005 Apr;2(2):231-8
references.pmid: 15974923
references.citation: PLoS Biol. 2009 Feb 17;7(2):e34
references.pmid: 19226187
references.citation: Nat Commun. 2011;2:252
references.pmid: 21427723
references.citation: Int J Alzheimers Dis. 2012;2012:731526
references.pmid: 22690349
references.citation: Neurobiol Dis. 2001 Feb;8(1):162-72
references.pmid: 11162250
references.citation: J Clin Invest. 2013 Oct;123(10):4158-69
references.pmid: 23999428
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):721-6
references.pmid: 12522269
references.citation: J Neurosci. 2010 Jan 13;30(2):591-9
references.pmid: 20071522
references.citation: Biochemistry. 2007 Mar 20;46(11):3055-64
references.pmid: 17311412
references.citation: Mol Neurodegener. 2010 Nov 01;5:45
references.pmid: 21040568
references.citation: FASEB J. 2009 Apr;23(4):1146-52
references.pmid: 19074508
references.citation: Mol Neurodegener. 2011 Jun 06;6:39
references.pmid: 21645391
references.citation: J Neurosci. 2006 Jun 28;26(26):6985-96
references.pmid: 16807328
references.citation: J Biol Chem. 2011 Jun 10;286(23):20512-24
references.pmid: 21498513
references.citation: Proc Natl Acad Sci U S A. 1975 May;72(5):1858-62
references.pmid: 1057175
references.citation: J Neurosci. 2005 Jun 1;25(22):5365-75
references.pmid: 15930385
references.citation: J Clin Invest. 2007 Mar;117(3):648-58
references.pmid: 17304350
references.citation: Nature. 1998 Jun 18;393(6686):702-5
references.pmid: 9641683
references.citation: FASEB J. 2006 Apr;20(6):753-5
references.pmid: 16464956
references.citation: Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006247
references.pmid: 22762014
references.citation: FASEB J. 2013 Apr;27(4):1450-9
references.pmid: 23271055
references.citation: Sci Rep. 2015 May 14;5:9659
references.pmid: 25974414
references.citation: Cell. 1997 Apr 18;89(2):297-308
references.pmid: 9108484
references.citation: Biochem Biophys Res Commun. 2001 Jan 12;280(1):249-58
references.pmid: 11162507
references.citation: Hum Mol Genet. 2014 Jan 1;23(1):104-16
references.pmid: 23962722
references.citation: Cell. 2014 Feb 27;156(5):963-74
references.pmid: 24581495
references.citation: J Biol Chem. 2001 Dec 21;276(51):48165-74
references.pmid: 11606569
references.citation: J Alzheimers Dis. 2008 Aug;14(4):401-9
references.pmid: 18688090
references.citation: Nat Rev Neurosci. 2016 Jan;17(1):5-21
references.pmid: 26631930
references.citation: Biochemistry. 2002 Dec 17;41(50):14885-96
references.pmid: 12475237
references.citation: Nat Rev Mol Cell Biol. 2004 Oct;5(10):781-91
references.pmid: 15459659
references.citation: Science. 2005 Jul 15;309(5733):476-81
references.pmid: 16020737
references.citation: FASEB J. 2015 Aug;29(8):3171-81
references.pmid: 25888602
references.citation: Proc Natl Acad Sci U S A. 1988 Jun;85(11):4051-5
references.pmid: 3131773
references.citation: Biochemistry. 2011 Nov 29;50(47):10300-10
references.pmid: 22039833
references.citation: J Biol Chem. 2006 Jul 14;281(28):19107-14
references.pmid: 16687396
references.citation: Biochemistry. 2006 Feb 21;45(7):2283-93
references.pmid: 16475817
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8463-7
references.pmid: 7667312
references.citation: J Biol Chem. 2005 Jul 1;280(26):24978-86
references.pmid: 15855160
references.citation: Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):7501-6
references.pmid: 26034266
references.citation: Nat Med. 2014 Nov;20(11):1254-62
references.pmid: 25326800
references.citation: Am J Pathol. 2006 May;168(5):1598-607
references.pmid: 16651626