6n37 | pdb_00006n37

SegA-sym, conformation of TDP-43 low complexity domain segment A sym

Loading... Status: waiting for Mol* initialization Structural highlights 6n37 is a 10 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: TARDBP, TDP43 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [TADBP_HUMAN] Defects in TARDBP are the cause of amyotrophic lateral sclerosis type 10 (ALS10) [MIM:612069]. ALS is a neurodegenerative disorder affecting upper and lower motor neurons and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of ALS is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Function [TADBP_HUMAN] DNA and RNA-binding protein which regulates transcription and splicing. Involved in the regulation of CFTR splicing. It promotes CFTR exon 9 skipping by binding to the UG repeated motifs in the polymorphic region near the 3'-splice site of this exon. The resulting aberrant splicing is associated with pathological features typical of cystic fibrosis. May also be involved in microRNA biogenesis, apoptosis and cell division. Can repress HIV-1 transcription by binding to the HIV-1 long terminal repeat. Stabilizes the low molecular weight neurofilament (NFL) mRNA through a direct interaction with the 3' UTR. Publication Abstract from PubMed The DNA and RNA processing protein TDP-43 undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates form reversible, transient species such as nuclear bodies, stress granules, and myo-granules. Pathogenic, irreversible TDP-43 aggregates form in amyotrophic lateral sclerosis and other neurodegenerative conditions. Here we find the features of TDP-43 fibrils that confer both reversibility and irreversibility by determining structures of two segments reported to be the pathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), which forms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues 286-331 containing the amyotrophic lateral sclerosis hereditary mutation A315E), which forms R-shaped folds. Energetic analysis suggests that the dagger-shaped polymorphs represent irreversible fibril structures, whereas the SegB polymorph may participate in both reversible and irreversible fibrils. Our structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology. Cryo-EM structures of four polymorphic TDP-43 amyloid cores.,Cao Q, Boyer DR, Sawaya MR, Ge P, Eisenberg DS Nat Struct Mol Biol. 2019 Jul;26(7):619-627. doi: 10.1038/s41594-019-0248-4. Epub, 2019 Jun 24. PMID:31235914 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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