An Amyloid-like Pathological Conformation of TDP-43 is Stabilized by Hypercooperative Hydrogen Bonds
TDP-43 is an essential RNA-binding protein forming aggregates in almost all cases of sporadic ALS and many cases of FTLD and other neurodegenerative diseases. TDP-43 consists of a folded N-terminal domain with a singular structure, two RRM RNA-binding domains, and a long disordered C-terminal regio...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-11-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnmol.2016.00125/full |
| _version_ | 1811281973060042752 |
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| author | Miguel Mompeán Marco Baralle Emanuele Buratti Douglas Vinson Laurents |
| author_facet | Miguel Mompeán Marco Baralle Emanuele Buratti Douglas Vinson Laurents |
| author_sort | Miguel Mompeán |
| collection | DOAJ |
| description | TDP-43 is an essential RNA-binding protein forming aggregates in almost all cases of sporadic ALS and many cases of FTLD and other neurodegenerative diseases. TDP-43 consists of a folded N-terminal domain with a singular structure, two RRM RNA-binding domains, and a long disordered C-terminal region which plays roles in functional RNA regulatory assemblies as well as pernicious aggregation. Evidence from pathological mutations and seeding experiments strongly suggest that TDP-43 aggregates are pathologically relevant through toxic gain-of-harmful-function and/or harmful loss-of-native-function mechanisms. Recent, but not early, microscopy studies and the ability of TDP-43 aggregates to resist harsh treatment and to seed new pathological aggregates in vitro and in cells strongly suggest that TDP-43 aggregates have a self-templating, amyloid-like structure. Based on the importance of the Gln/Asn-rich 341–367 residue segment for efficient aggregation of endogenous TDP-43 when presented as a 12X-repeat and extensive spectroscopic and computational experiments, we recently proposed that this segment adopts a beta-hairpin structure that assembles in a parallel with a beta-turn configuration to form an amyloid-like structure. Here, we propose that this conformer is stabilized by an especially strong class of hypercooperative hydrogen bonding unique to Gln and Asn sidechains. The clinical existence of this conformer is supported by very recent LC-MS/MS characterization of TDP-43 from ex-vivo aggregates, which show that residues 341-367 were protected in vivo from Ser phosphorylation, Gln/Asn deamidation and Met oxidation. Its distinct pattern of SDS-PAGE bands allows us to link this conformer to the exceptionally stable seed of the Type A TDP-43 proteinpathy. |
| first_indexed | 2024-04-13T01:44:24Z |
| format | Article |
| id | doaj.art-97e47977779940138bec5aa57e07646d |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-13T01:44:24Z |
| publishDate | 2016-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-97e47977779940138bec5aa57e07646d2022-12-22T03:08:06ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992016-11-01910.3389/fnmol.2016.00125220141An Amyloid-like Pathological Conformation of TDP-43 is Stabilized by Hypercooperative Hydrogen BondsMiguel Mompeán0Marco Baralle1Emanuele Buratti2Douglas Vinson Laurents3Instituto de Química Física Rocasolano CSICInternational Centre for Genetic Engineering and Biotechnology (ICGEB)International Centre for Genetic Engineering and Biotechnology (ICGEB)Instituto de Química Física Rocasolano CSICTDP-43 is an essential RNA-binding protein forming aggregates in almost all cases of sporadic ALS and many cases of FTLD and other neurodegenerative diseases. TDP-43 consists of a folded N-terminal domain with a singular structure, two RRM RNA-binding domains, and a long disordered C-terminal region which plays roles in functional RNA regulatory assemblies as well as pernicious aggregation. Evidence from pathological mutations and seeding experiments strongly suggest that TDP-43 aggregates are pathologically relevant through toxic gain-of-harmful-function and/or harmful loss-of-native-function mechanisms. Recent, but not early, microscopy studies and the ability of TDP-43 aggregates to resist harsh treatment and to seed new pathological aggregates in vitro and in cells strongly suggest that TDP-43 aggregates have a self-templating, amyloid-like structure. Based on the importance of the Gln/Asn-rich 341–367 residue segment for efficient aggregation of endogenous TDP-43 when presented as a 12X-repeat and extensive spectroscopic and computational experiments, we recently proposed that this segment adopts a beta-hairpin structure that assembles in a parallel with a beta-turn configuration to form an amyloid-like structure. Here, we propose that this conformer is stabilized by an especially strong class of hypercooperative hydrogen bonding unique to Gln and Asn sidechains. The clinical existence of this conformer is supported by very recent LC-MS/MS characterization of TDP-43 from ex-vivo aggregates, which show that residues 341-367 were protected in vivo from Ser phosphorylation, Gln/Asn deamidation and Met oxidation. Its distinct pattern of SDS-PAGE bands allows us to link this conformer to the exceptionally stable seed of the Type A TDP-43 proteinpathy.http://journal.frontiersin.org/Journal/10.3389/fnmol.2016.00125/fullFrontotemporal Lobar DegenerationProtein misfolding and DiseaseAmyotrophic lateral sclerosis (ALS)hnRNPsPathological Amyloidstransitive response DNA-bonding Protein 43kDa (TDP-43) |
| spellingShingle | Miguel Mompeán Marco Baralle Emanuele Buratti Douglas Vinson Laurents An Amyloid-like Pathological Conformation of TDP-43 is Stabilized by Hypercooperative Hydrogen Bonds Frontiers in Molecular Neuroscience Frontotemporal Lobar Degeneration Protein misfolding and Disease Amyotrophic lateral sclerosis (ALS) hnRNPs Pathological Amyloids transitive response DNA-bonding Protein 43kDa (TDP-43) |
| title | An Amyloid-like Pathological Conformation of TDP-43 is Stabilized by Hypercooperative Hydrogen Bonds |
| title_full | An Amyloid-like Pathological Conformation of TDP-43 is Stabilized by Hypercooperative Hydrogen Bonds |
| title_fullStr | An Amyloid-like Pathological Conformation of TDP-43 is Stabilized by Hypercooperative Hydrogen Bonds |
| title_full_unstemmed | An Amyloid-like Pathological Conformation of TDP-43 is Stabilized by Hypercooperative Hydrogen Bonds |
| title_short | An Amyloid-like Pathological Conformation of TDP-43 is Stabilized by Hypercooperative Hydrogen Bonds |
| title_sort | amyloid like pathological conformation of tdp 43 is stabilized by hypercooperative hydrogen bonds |
| topic | Frontotemporal Lobar Degeneration Protein misfolding and Disease Amyotrophic lateral sclerosis (ALS) hnRNPs Pathological Amyloids transitive response DNA-bonding Protein 43kDa (TDP-43) |
| url | http://journal.frontiersin.org/Journal/10.3389/fnmol.2016.00125/full |
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