2N4H
Solution Structure of the Q343R Mutant of TDP-43 Amyloidogenic Core Region
Summary for 2N4H
| Entry DOI | 10.2210/pdb2n4h/pdb |
| Related | 2N3X 2N4G |
| NMR Information | BMRB: 25668 |
| Descriptor | TAR DNA-binding protein 43 (1 entity in total) |
| Functional Keywords | tdp-43, amyloidogenic core region, q343r, dna binding protein |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus : Q13148 |
| Total number of polymer chains | 1 |
| Total formula weight | 5236.86 |
| Authors | |
| Primary citation | Jiang, L.L.,Zhao, J.,Yin, X.F.,He, W.T.,Yang, H.,Che, M.X.,Hu, H.Y. Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation Sci Rep, 6:23928-23928, 2016 Cited by PubMed Abstract: TDP-43 is a DNA/RNA binding protein associated with TDP-43 proteinopathies. Many mutations have been identified in the flexible C-terminal region, which is implicated in the disease pathology. We investigated four point mutations in the amyloidogenic core region (residues 311-360) of TDP-43 by biochemical and spectroscopic methods. We found that the G335D mutation enhances the aggregation and inclusion formation of TDP-43 and this mutant in TDP-35 (the C-terminal fragment of 35 kDa) exaggerates the antagonist effect on RNA processing by endogenous TDP-43; whereas Q343R gives an opposite effect. As a comparison, M337V and Q331K have very little impact on the aggregation and inclusion formation of TDP-43 or TDP-35. NMR structural analysis showed that the G335D mutant in the core region forms a loop linker between the two α-helices and promotes α-to-β transition, but Q343R loses the second helix and consequently the structural transformation. Thus, the propensity of structural transformation in the amyloidogenic core of TDP-43 determines its aggregation and inclusion formation. This study may provide a molecular mechanism of the TDP-43 proteinopathies caused by genetic mutations. PubMed: 27030292DOI: 10.1038/srep23928 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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