Protonation-deprotonation switch controls the amyloid-like misfolding of nucleic-acid-binding domains of TDP-43
| Title | Protonation-deprotonation switch controls the amyloid-like misfolding of nucleic-acid-binding domains of TDP-43 |
| Publication Type | Journal Article |
| Year of Publication | 2021 |
| Authors | Patni, D, Jha, SKumar |
| Journal | Journal of Physical Chemistry B |
| Volume | 125 |
| Issue | 30 |
| Pagination | 8383-8394 |
| Date Published | AUG |
| Type of Article | Article |
| ISSN | 1520-6106 |
| Abstract | Nutrient starvation stress acidifies the cytosol and leads to the formation of large protein assemblies and misfolded aggregates. However, how starvation stress is sensed at the molecular level and leads to protein misfolding is poorly understood. TDP-43 is a vital protein, which, under stress-like conditions, associates with stress granule proteins via its functional nucleic-acid-binding domains (TDP-43(t)(RRM)) and misfolds to form aberrant aggregates. Here, we show that the monomeric N form of TDP-43(t)(RRM) forms a misfolded amyloid-like protein assembly, beta form, in a pH-dependent manner and identified the critical protein side-chain residue whose protonation triggers its misfolding. We systematically mutated the three buried ionizable residues, D105, H166, and H256, to neutral amino acids to block the pH-dependent protonation-deprotonation titration of their side chain and studied their effect on the N-to-beta transition. We observed that D105A and H2S6Q resembled TDP-43(t)(RRM) in their pH-dependent misfolding behavior. However, H166Q retains the N-like secondary structure under low-pH conditions and does not show pH-dependent misfolding to the beta form. These results indicate that H166 is the critical side-chain residue whose protonation triggers the misfolding of TDP-43(t)(RRM) and shed light on how stress-induced misfolding of proteins during neurodegeneration could begin from site-specific triggers. |
| DOI | 10.1021/acs.jpcb.1c03262 |
| Type of Journal (Indian or Foreign) | Foreign |
| Impact Factor (IF) | 2.991 |
Divison category:
Physical and Materials Chemistry
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