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Structural analysis of disease-related TDP-43 D169G mutation: linking enhanced stability and caspase cleavage efficiency to protein accumulation.

<div class='caption-title'>TDP-43 domain structure and the ALS-linked mutations.</div>
<div class='caption-title'>TDP-43 D169G mutants are more resistant to thermal denaturation as monitored by circular dichroism.</div>
<div class='caption-title'>TDP-43 D169G mutants are more resistant to thermal unfolding as monitored by differential scanning fluorimetry.</div>
Chiang CH, Grauffel C, Wu LS, Kuo PH, Doudeva LG, Lim C, Shen CK, Yuan HS
OpenAccess logo Sci Rep 6 21581 (2016)
Cited: 34 times
EuropePMC logo PMID: 26883171

Abstract

The RNA-binding protein TDP-43 forms intracellular inclusions in amyotrophic lateral sclerosis (ALS). While TDP-43 mutations have been identified in ALS patients, how these mutations are linked to ALS remains unclear. Here we examined the biophysical properties of six ALS-linked TDP-43 mutants and found that one of the mutants, D169G, had higher thermal stability than wild-type TDP-43 and that it was cleaved by caspase 3 more efficiently, producing increased levels of the C-terminal 35 kD fragments (TDP-35) in vitro and in neuroblastoma cells. The crystal structure of the TDP-43 RRM1 domain containing the D169G mutation in complex with DNA along with molecular dynamics simulations reveal that the D169G mutation induces a local conformational change in a β turn and increases the hydrophobic interactions in the RRM1 core, thus enhancing the thermal stability of the RRM1 domain. Our results provide the first crystal structure of TDP-43 containing a disease-linked D169G mutation and a disease-related mechanism showing that D169G mutant is more susceptible to proteolytic cleavage by caspase 3 into the pathogenic C-terminal 35-kD fragments due to its increased stability in the RRM1 domain. Modulation of TDP-43 stability and caspase cleavage efficiency could present an avenue for prevention and treatment of TDP-43-linked neurodegeneration.

Reviews - 4y0f mentioned but not cited (1)

  1. Structural Insights Into TDP-43 and Effects of Post-translational Modifications. François-Moutal L, Perez-Miller S, Scott DD, Miranda VG, Mollasalehi N, Khanna M. Front Mol Neurosci 12 301 (2019)

Articles - 4y0f mentioned but not cited (4)

  1. Structural analysis of disease-related TDP-43 D169G mutation: linking enhanced stability and caspase cleavage efficiency to protein accumulation. Chiang CH, Grauffel C, Wu LS, Kuo PH, Doudeva LG, Lim C, Shen CK, Yuan HS. Sci Rep 6 21581 (2016)
  2. RNA recognition motifs of disease-linked RNA-binding proteins contribute to amyloid formation. Agrawal S, Kuo PH, Chu LY, Golzarroshan B, Jain M, Yuan HS. Sci Rep 9 6171 (2019)
  3. Cytoplasmic Relocalization of TAR DNA-Binding Protein 43 Is Not Sufficient to Reproduce Cellular Pathologies Associated with ALS In vitro. Wobst HJ, Wesolowski SS, Chadchankar J, Delsing L, Jacobsen S, Mukherjee J, Deeb TZ, Dunlop J, Brandon NJ, Moss SJ. Front Mol Neurosci 10 46 (2017)
  4. Frontotemporal dementia-linked P112H mutation of TDP-43 induces protein structural change and impairs its RNA binding function. Agrawal S, Jain M, Yang WZ, Yuan HS. Protein Sci 30 350-365 (2021)


Reviews citing this publication (10)

  1. Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis. Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK. Front Mol Neurosci 12 25 (2019)
  2. The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD. Berning BA, Walker AK. Front Neurosci 13 335 (2019)
  3. Linking hnRNP Function to ALS and FTD Pathology. Purice MD, Taylor JP. Front Neurosci 12 326 (2018)
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  5. The roles of intrinsic disorder-based liquid-liquid phase transitions in the "Dr. Jekyll-Mr. Hyde" behavior of proteins involved in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Uversky VN. Autophagy 13 2115-2162 (2017)
  6. Computational Approaches to Prioritize Cancer Driver Missense Mutations. Zhao F, Zheng L, Goncearenco A, Panchenko AR, Li M. Int J Mol Sci 19 E2113 (2018)
  7. Molecular, functional, and pathological aspects of TDP-43 fragmentation. Chhangani D, Martín-Peña A, Rincon-Limas DE. iScience 24 102459 (2021)
  8. Importin α/β and the tug of war to keep TDP-43 in solution: quo vadis? Doll SG, Cingolani G. Bioessays 44 e2200181 (2022)
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  1. Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Guenther EL, Cao Q, Trinh H, Lu J, Sawaya MR, Cascio D, Boyer DR, Rodriguez JA, Hughes MP, Eisenberg DS. Nat Struct Mol Biol 25 463-471 (2018)
  2. PremPS: Predicting the impact of missense mutations on protein stability. Chen Y, Lu H, Zhang N, Zhu Z, Wang S, Li M. PLoS Comput Biol 16 e1008543 (2020)
  3. Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates. Garnier C, Devred F, Byrne D, Puppo R, Roman AY, Malesinski S, Golovin AV, Lebrun R, Ninkina NN, Tsvetkov PO. Sci Rep 7 6812 (2017)
  4. Intrinsic disorder in proteins involved in amyotrophic lateral sclerosis. Santamaria N, Alhothali M, Alfonso MH, Breydo L, Uversky VN. Cell Mol Life Sci 74 1297-1318 (2017)
  5. Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises. McAlary L, Chew YL, Lum JS, Geraghty NJ, Yerbury JJ, Cashman NR. Front Cell Neurosci 14 581907 (2020)
  6. Truncation of the TAR DNA-binding protein 43 is not a prerequisite for cytoplasmic relocalization, and is suppressed by caspase inhibition and by introduction of the A90V sequence variant. Wobst HJ, Delsing L, Brandon NJ, Moss SJ. PLoS One 12 e0177181 (2017)
  7. SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution. Maraschi A, Gumina V, Dragotto J, Colombrita C, Mompeán M, Buratti E, Silani V, Feligioni M, Ratti A. Mol Neurobiol 58 5682-5702 (2021)
  8. Comparative analysis of thermal unfolding simulations of RNA recognition motifs (RRMs) of TAR DNA-binding protein 43 (TDP-43). Prakash A, Kumar V, Meena NK, Hassan MI, Lynn AM. J Biomol Struct Dyn 37 178-194 (2019)
  9. Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43. Vivoli-Vega M, Guri P, Chiti F, Bemporad F. Int J Mol Sci 21 E6259 (2020)
  10. Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43. Garcia Morato J, Hans F, von Zweydorf F, Feederle R, Elsässer SJ, Skodras AA, Gloeckner CJ, Buratti E, Neumann M, Kahle PJ. Nat Commun 13 1223 (2022)
  11. Purification and Structural Characterization of Aggregation-Prone Human TDP-43 Involved in Neurodegenerative Diseases. Wright GSA, Watanabe TF, Amporndanai K, Plotkin SS, Cashman NR, Antonyuk SV, Hasnain SS. iScience 23 101159 (2020)
  12. A context-based ABC model for literature-based discovery. Kim YH, Song M. PLoS One 14 e0215313 (2019)
  13. Atypical TDP-43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP. Cooper-Knock J, Julian TH, Feneberg E, Highley JR, Sidra M, Turner MR, Talbot K, Ansorge O, Allen SP, Moll T, Shelkovnikova T, Castelli L, Hautbergue GM, Hewitt C, Kirby J, Wharton SB, Mead RJ, Shaw PJ. Brain Pathol 33 e13104 (2023)
  14. Exploring the use of molecular dynamics in assessing protein variants for phenotypic alterations. Garg A, Pal D. Hum Mutat 40 1424-1435 (2019)
  15. Intrinsic protein disorder could be overlooked in cocrystallization conditions: An SRCD case study. Németh E, Balogh RK, Borsos K, Czene A, Thulstrup PW, Gyurcsik B. Protein Sci 25 1977-1988 (2016)
  16. Effects of intracellular calcium accumulation on proteins encoded by the major genes underlying amyotrophic lateral sclerosis. De Marco G, Lomartire A, Manera U, Canosa A, Grassano M, Casale F, Fuda G, Salamone P, Rinaudo MT, Colombatto S, Moglia C, Chiò A, Calvo A. Sci Rep 12 395 (2022)
  17. Codon-optimized TDP-43 mediates neurodegeneration in a Drosophila model of ALS/FTLD. Yusuff T, Chang YC, Sang TK, Jackson GR, Chatterjee S. Front Genet 14 881638 (2023)
  18. Investigation of the proton relay system operative in human cystosolic aminopeptidase P. Chang HC, Kung CC, Chang TT, Jao SC, Hsu YT, Li WS, Li WS. PLoS One 13 e0190816 (2018)
  19. RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy. Necarsulmer JC, Simon JM, Evangelista BA, Chen Y, Tian X, Nafees S, Marquez AB, Jiang H, Wang P, Ajit D, Nikolova VD, Harper KM, Ezzell JA, Lin FC, Beltran AS, Moy SS, Cohen TJ. Elife 12 RP85921 (2023)


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