title: Inter-domain interactions of TDP-43 as decoded by NMR.
abstract: TDP-43 inclusions have been found in ∼97% ALS as well as an increasing spectrum of other neurodegenerative diseases including Alzheimer's. TDP-43 contains an ubiquitin-like fold, two RRMs and a prion-like domain, but whether they interact with each other remains unknown due to being intrinsically aggregation-prone. Nevertheless, this knowledge is pivotal to understanding physiological functions and pathological roles of TDP-43. Here as facilitated by our previous discovery which allowed NMR characterization of TDP-43 and its five dissected fragments, we successfully decoded that TDP-43 does have dynamic inter-domain interactions, which are coordinated by the intrinsically-disordered prion-like domain. Thus, TDP-43 appears to undergo conformational exchanges between "closed" and "open" states which are needed for its functions. Our study thus offers a mechanism by which cellular processes might control TDP-43 physiology and proteinopathy by mediating its inter-domain interactions.
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.
authors.forename: Liangzhong
authors.initials: L
authors.lastname: Lim
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260. Electronic address: dbssjx@nus.edu.sg.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Song
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry*; D057180:Frontotemporal Dementia / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs
chemical_list: D004268:DNA-Binding Proteins; D011328:Prions; C000598624:TARDBP protein, human
keywords: Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia (FTD); Inter-domain interaction; NMR spectroscopy; Prion-like domain; TDP-43