ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain

Alami, 2014, Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations, Neuron, 81, 536, 10.1016/j.neuron.2013.12.018 Altmeyer, 2015, Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose), Nat. Commun., 6, 8088, 10.1038/ncomms9088 Amador-Ortiz, 2007, TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease, Ann. Neurol., 61, 435, 10.1002/ana.21154 Arnold, 2013, ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43, Proc. Natl. Acad. Sci. USA, 110, E736, 10.1073/pnas.1222809110 Ash, 2010, Neurotoxic effects of TDP-43 overexpression in C. elegans, Hum. Mol. Genet., 19, 3206, 10.1093/hmg/ddq230 Ayala, 2005, Human, Drosophila, and C. elegans TDP43: nucleic acid binding properties and splicing regulatory function, J. Mol. Biol., 348, 575, 10.1016/j.jmb.2005.02.038 Beck, 2011, The quantitative proteome of a human cell line, Mol. Syst. Biol., 7, 549, 10.1038/msb.2011.82 Bentmann, 2012, Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43), J. Biol. Chem., 287, 23079, 10.1074/jbc.M111.328757 Best, 2014, Balanced protein-water interactions improve properties of disordered proteins and non-specific protein association, J. Chem. Theory Comput., 10, 5113, 10.1021/ct500569b Brangwynne, 2009, Germline P granules are liquid droplets that localize by controlled dissolution/condensation, Science, 324, 1729, 10.1126/science.1172046 Budini, 2012, Role of selected mutations in the Q/N rich region of TDP-43 in EGFP-12xQ/N-induced aggregate formation, Brain Res., 1462, 139, 10.1016/j.brainres.2012.02.031 Budini, 2015, TDP-43 loss of cellular function through aggregation requires additional structural determinants beyond its C-terminal Q/N prion-like domain, Hum. Mol. Genet., 24, 9, 10.1093/hmg/ddu415 Buratti, 2015, Functional significance of TDP-43 mutations in disease, Adv. Genet., 91, 1, 10.1016/bs.adgen.2015.07.001 Buratti, 2001, Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping, EMBO J., 20, 1774, 10.1093/emboj/20.7.1774 Buratti, 2005, TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing, J. Biol. Chem., 280, 37572, 10.1074/jbc.M505557200 Burke, 2015, Residue-by-residue view of in vitro FUS granules that bind the C-Terminal domain of RNA polymerase II, Mol. Cell, 60, 231, 10.1016/j.molcel.2015.09.006 Chang, 2012, The N-terminus of TDP-43 promotes its oligomerization and enhances DNA binding affinity, Biochem. Biophys. Res. Commun., 425, 219, 10.1016/j.bbrc.2012.07.071 Colombrita, 2009, TDP-43 is recruited to stress granules in conditions of oxidative insult, J. Neurochem., 111, 1051, 10.1111/j.1471-4159.2009.06383.x D'Alton, 2014, Divergent phenotypes in mutant TDP-43 transgenic mice highlight potential confounds in TDP-43 transgenic modeling, PLoS One, 9, e86513, 10.1371/journal.pone.0086513 D'Ambrogio, 2009, Functional mapping of the interaction between TDP-43 and hnRNP A2 in vivo, Nucleic Acids Res., 37, 4116, 10.1093/nar/gkp342 Dammer, 2012, Coaggregation of RNA-binding proteins in a model of TDP-43 proteinopathy with selective RGG motif methylation and a role for RRM1 ubiquitination, PLoS One, 7, e38658, 10.1371/journal.pone.0038658 Daura, 1999, Peptide folding: when simulation meets experiment, Angew. Chem. Int. Ed. Engl., 38, 236, 10.1002/(SICI)1521-3773(19990115)38:1/2<236::AID-ANIE236>3.0.CO;2-M Deighan, 2012, Efficient simulation of explicitly solvated proteins in the well-tempered ensemble, J. Chem. Theory Comput., 8, 2189, 10.1021/ct300297t Estes, 2011, Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS, Hum. Mol. Genet., 20, 2308, 10.1093/hmg/ddr124 Freibaum, 2010, Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery, J. Proteome Res., 9, 1104, 10.1021/pr901076y Iglesias, 2013, SS-map, Intrinsically Disord. Proteins, 1, e25323, 10.4161/idp.25323 Jain, 2016, ATPase-modulated stress granules contain a diverse proteome and substructure, Cell, 164, 487, 10.1016/j.cell.2015.12.038 Jiang, 2013, Structural transformation of the amyloidogenic core region of TDP-43 protein initiates its aggregation and cytoplasmic inclusion, J. Biol. Chem., 288, 19614, 10.1074/jbc.M113.463828 Jiang, 2016, Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation, Sci. Rep., 6, 23928, 10.1038/srep23928 Johnson, 2009, TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity, J. Biol. Chem., 284, 20329, 10.1074/jbc.M109.010264 Kabsch, 1983, Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features, Biopolymers, 22, 2577, 10.1002/bip.360221211 Kametani, 2009, Identification of casein kinase-1 phosphorylation sites on TDP-43, Biochem. Biophys. Res. Commun., 382, 405, 10.1016/j.bbrc.2009.03.038 Kato, 2012, Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels, Cell, 149, 753, 10.1016/j.cell.2012.04.017 King, 2012, The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease, Brain Res., 1462, 61, 10.1016/j.brainres.2012.01.016 Kwon, 2012, Screening of the SOD1, FUS, TARDBP, ANG, and OPTN mutations in Korean patients with familial and sporadic ALS, Neurobiol. Aging, 33, 1017.e17, 10.1016/j.neurobiolaging.2011.12.003 Kwon, 2013, The RNA-binding protein repertoire of embryonic stem cells, Nat. Struct. Mol. Biol., 20, 1122, 10.1038/nsmb.2638 Libich, 2013, Probing the transient dark state of substrate binding to GroEL by relaxation-based solution NMR, Proc. Natl. Acad. Sci. USA, 110, 11361, 10.1073/pnas.1305715110 Lim, 2016, ALS-causing mutations significantly perturb the self-assembly and interaction with nucleic acid of the intrinsically disordered prion-like domain of TDP-43, PLoS Biol., 14, e1002338, 10.1371/journal.pbio.1002338 Lin, 2015, Formation and maturation of phase-separated liquid droplets by RNA-binding proteins, Mol. Cell, 60, 208, 10.1016/j.molcel.2015.08.018 Ling, 2013, Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis, Neuron, 79, 416, 10.1016/j.neuron.2013.07.033 Lukavsky, 2013, Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43, Nat. Struct. Mol. Biol., 20, 1443, 10.1038/nsmb.2698 Marsh, 2006, Sensitivity of secondary structure propensities to sequence differences between alpha- and gamma-synuclein: implications for fibrillation, Protein Sci., 15, 2795, 10.1110/ps.062465306 Mitrea, 2016, Phase separation in biology; functional organization of a higher order, Cell Commun. Signal., 14, 1, 10.1186/s12964-015-0125-7 Mittal, 2013, Structural ensemble of an intrinsically disordered polypeptide, J. Phys. Chem. B, 117, 118, 10.1021/jp308984e Molliex, 2015, Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization, Cell, 163, 123, 10.1016/j.cell.2015.09.015 Mompean, 2014, Structural characterization of the minimal segment of TDP-43 competent for aggregation, Arch. Biochem. Biophys., 545, 53, 10.1016/j.abb.2014.01.007 Mompean, 2016, The TDP-43 N-terminal domain structure at high resolution, FEBS J., 283, 1242, 10.1111/febs.13651 Neumann, 2006, Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis, Science, 314, 130, 10.1126/science.1134108 Nonaka, 2016, Phosphorylation of TAR DNA-binding protein of 43 kDa (TDP-43) by truncated casein kinase 1δ triggers mislocalization and accumulation of TDP-43, J. Biol. Chem., 291, 5473, 10.1074/jbc.M115.695379 Nott, 2015, Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles, Mol. Cell, 57, 936, 10.1016/j.molcel.2015.01.013 Patel, 2015, A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation, Cell, 162, 1066, 10.1016/j.cell.2015.07.047 Peti, 2007, Strategies to maximize heterologous protein expression in Escherichia coli with minimal cost, Protein Expr. Purif., 51, 1, 10.1016/j.pep.2006.06.024 Phan, 2011, Structure-function studies of FMRP RGG peptide recognition of an RNA duplex-quadruplex junction, Nat. Struct. Mol. Biol., 18, 796, 10.1038/nsmb.2064 Schwartz, 2013, RNA seeds higher-order assembly of FUS protein, Cell Rep., 5, 918, 10.1016/j.celrep.2013.11.017 Shen, 2010, SPARTA+: a modest improvement in empirical NMR chemical shift prediction by means of an artificial neural network, J. Biomol. NMR, 48, 13, 10.1007/s10858-010-9433-9 Smith, 1996, Analysis of main chain torsion angles in proteins: prediction of NMR coupling constants for native and random coil conformations, J. Mol. Biol., 255, 494, 10.1006/jmbi.1996.0041 Sormanni, 2015, The δ2D method: simultaneous sequence-based prediction of the statistical populations of ordered and disordered regions in proteins, J. Mol. Biol., 427, 982, 10.1016/j.jmb.2014.12.007 Tang, 2006, Visualization of transient encounter complexes in protein-protein association, Nature, 444, 383, 10.1038/nature05201 Vogeli, 2007, Limits on variations in protein backbone dynamics from precise measurements of scalar couplings, J. Am. Chem. Soc., 129, 9377, 10.1021/ja070324o Volkov, 2006, Solution structure and dynamics of the complex between cytochrome c and cytochrome c peroxidase determined by paramagnetic NMR, Proc. Natl. Acad. Sci. USA, 103, 18945, 10.1073/pnas.0603551103 Wang, 2002, Probability-based protein secondary structure identification using combined NMR chemical-shift data, Protein Sci., 11, 852, 10.1110/ps.3180102 Wang, 2001, CPMG sequences with enhanced sensitivity to chemical exchange, J. Biomol. NMR, 21, 361, 10.1023/A:1013328206498 Wang, 2013, The truncated C-terminal RNA recognition motif of TDP-43 protein plays a key role in forming proteinaceous aggregates, J. Biol. Chem., 288, 9049, 10.1074/jbc.M112.438564 Wegorzewska, 2009, TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration, Proc. Natl. Acad. Sci. USA, 106, 18809, 10.1073/pnas.0908767106 Wishart, 1992, The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy, Biochemistry, 31, 1647, 10.1021/bi00121a010 Xiang, 2015, The LC domain of hnRNPA2 adopts similar conformations in hydrogel polymers, liquid-like droplets, and nuclei, Cell, 163, 829, 10.1016/j.cell.2015.10.040 Zerze, 2015, Sequence- and temperature-dependent properties of unfolded and disordered proteins from atomistic simulations, J. Phys. Chem. B, 119, 14622, 10.1021/acs.jpcb.5b08619 Zhang, 2003, RefDB: a database of uniformly referenced protein chemical shifts, J. Biomol. NMR, 25, 173, 10.1023/A:1022836027055