| Structural highlights
Disease
[TOR1A_HUMAN] Myoclonus-dystonia syndrome;Early-onset generalized limb-onset dystonia. The disease is caused by mutations affecting the gene represented in this entry.
Function
[TOR1A_HUMAN] Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates. Involved in the regulation of synaptic vesicle recycling, controls STON2 protein stability in collaboration with the COP9 signalosome complex (CSN). In the nucleus, may link the cytoskeleton with the nuclear envelope, this mechanism seems to be crucial for the control of nuclear polarity, cell movement and, specifically in neurons, nuclear envelope integrity. Participates in the cellular trafficking and may regulate the subcellular location of multipass membrane proteins such as the dopamine transporter SLC6A3, leading to the modulation of dopamine neurotransmission. In the endoplasmic reticulum, plays a role in the quality control of protein folding by increasing clearance of misfolded proteins such as SGCE variants or holding them in an intermediate state for proper refolding. May have a redundant function with TOR1B in non-neural tissues.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
TorsinA is an ER-resident AAA + ATPase, whose deletion of glutamate E303 results in the genetic neuromuscular disease primary dystonia. TorsinA is an unusual AAA + ATPase that needs an external activator. Also, it likely does not thread a peptide substrate through a narrow central channel, in contrast to its closest structural homologs. Here, we examined the oligomerization of TorsinA to get closer to a molecular understanding of its still enigmatic function. We observe TorsinA to form helical filaments, which we analyzed by cryo-electron microscopy using helical reconstruction. The 4.4 A structure reveals long hollow tubes with a helical periodicity of 8.5 subunits per turn, and an inner channel of ~ 4 nm diameter. We further show that the protein is able to induce tubulation of membranes in vitro, an observation that may reflect an entirely new characteristic of AAA + ATPases. We discuss the implications of these observations for TorsinA function.
The AAA + ATPase TorsinA polymerizes into hollow helical tubes with 8.5 subunits per turn.,Demircioglu FE, Zheng W, McQuown AJ, Maier NK, Watson N, Cheeseman IM, Denic V, Egelman EH, Schwartz TU Nat Commun. 2019 Jul 22;10(1):3262. doi: 10.1038/s41467-019-11194-w. PMID:31332180[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Torres GE, Sweeney AL, Beaulieu JM, Shashidharan P, Caron MG. Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15650-5. Epub 2004 Oct 25. PMID:15505207 doi:http://dx.doi.org/10.1073/pnas.0308088101
- ↑ Hewett JW, Zeng J, Niland BP, Bragg DC, Breakefield XO. Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics. Neurobiol Dis. 2006 Apr;22(1):98-111. Epub 2005 Dec 19. PMID:16361107 doi:http://dx.doi.org/10.1016/j.nbd.2005.10.012
- ↑ Hewett JW, Tannous B, Niland BP, Nery FC, Zeng J, Li Y, Breakefield XO. Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells. Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7271-6. Epub 2007 Apr 11. PMID:17428918 doi:http://dx.doi.org/10.1073/pnas.0701185104
- ↑ Granata A, Watson R, Collinson LM, Schiavo G, Warner TT. The dystonia-associated protein torsinA modulates synaptic vesicle recycling. J Biol Chem. 2008 Mar 21;283(12):7568-79. doi: 10.1074/jbc.M704097200. Epub 2007 , Dec 31. PMID:18167355 doi:http://dx.doi.org/10.1074/jbc.M704097200
- ↑ Nery FC, Zeng J, Niland BP, Hewett J, Farley J, Irimia D, Li Y, Wiche G, Sonnenberg A, Breakefield XO. TorsinA binds the KASH domain of nesprins and participates in linkage between nuclear envelope and cytoskeleton. J Cell Sci. 2008 Oct 15;121(Pt 20):3476-86. doi: 10.1242/jcs.029454. Epub 2008, Sep 30. PMID:18827015 doi:http://dx.doi.org/10.1242/jcs.029454
- ↑ Vander Heyden AB, Naismith TV, Snapp EL, Hodzic D, Hanson PI. LULL1 retargets TorsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. Mol Biol Cell. 2009 Jun;20(11):2661-72. doi: 10.1091/mbc.E09-01-0094. Epub 2009, Apr 1. PMID:19339278 doi:http://dx.doi.org/10.1091/mbc.E09-01-0094
- ↑ Burdette AJ, Churchill PF, Caldwell GA, Caldwell KA. The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro. Cell Stress Chaperones. 2010 Sep;15(5):605-17. doi: 10.1007/s12192-010-0173-2., Epub 2010 Feb 19. PMID:20169475 doi:http://dx.doi.org/10.1007/s12192-010-0173-2
- ↑ Zhao C, Brown RS, Chase AR, Eisele MR, Schlieker C. Regulation of Torsin ATPases by LAP1 and LULL1. Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):E1545-54. doi:, 10.1073/pnas.1300676110. Epub 2013 Apr 8. PMID:23569223 doi:http://dx.doi.org/10.1073/pnas.1300676110
- ↑ Demircioglu FE, Zheng W, McQuown AJ, Maier NK, Watson N, Cheeseman IM, Denic V, Egelman EH, Schwartz TU. The AAA + ATPase TorsinA polymerizes into hollow helical tubes with 8.5 subunits per turn. Nat Commun. 2019 Jul 22;10(1):3262. doi: 10.1038/s41467-019-11194-w. PMID:31332180 doi:http://dx.doi.org/10.1038/s41467-019-11194-w
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