TABLE 1.
Summary of potentiating Hsp104 mutations. The mutations that potentiate Hsp104 activity, their location, and their properties are listed based on61,63,107
| Potentiating Mutations | Middle domain helix | Properties |
|---|---|---|
| V426G | 1 | Suppresses toxicity of FUS |
| V426L | 1 | Suppresses toxicity of TDP-43, FUS, and α-syn; Does not modify EWSR1 toxicity; Restores nuclear TDP-43 and clears FUS and α-syn aggregates |
| A437W | Loop between 1 and 2 | Suppresses toxicity of TDP-43, FUS, and α-syn; Enhances EWSR1 toxicity |
| D498V | 3 | Suppresses toxicity of FUS and α-syn; Does not modify TDP-43 toxicity; ATPase similar to WT Hsp104; Does not require Hsp70 and Hsp40 for disaggregase activity; Hsp70 and Hsp40 do not stimulate disaggregase activity |
| A503X* | 3 | Suppress toxicity of TDP-43, FUS, and α-syn |
| A503V | 3 | Suppresses toxicity of TDP-43, FUS, and α-syn; Enhances EWSR1 toxicity; Elevated ATPase, disaggregase, translocase, and unfoldase activity; Does not require Hsp70 and Hsp40 for disaggregase activity; Restores nuclear TDP-43 and clears FUS and α-syn aggregates |
| A503S | 3 | Suppresses toxicity of TDP-43, FUS, TAF15, and α-syn; Enhances EWSR1 toxicity; Elevated ATPase, disaggregase, and unfoldase activity; Does not require Hsp70 and Hsp40 for disaggregase activity; Suppresses neurodegeneration in C. elegans PD model |
| A503V-DPLF | 3 (Plus pore loop Y257F in NBD1 and Y662F in NBD2) | Suppresses toxicity of TDP-43, FUS, and α-syn; Enhances EWSR1 toxicity; Elevated ATPase, disaggregase, and unfoldase activity; Does not require Hsp70 and Hsp40 for disaggregase activity; Suppresses neurodegeneration in C. elegans PD model |
| D504V | 3 | Suppresses toxicity of TDP-43, FUS, and α-syn |
| D504C | 3 | Suppresses toxicity of FUS, and α-syn; Does not modify TDP-43 toxicity; ATPase activity similar to WT Hsp104; Elevated disaggregase and unfoldase activity; Does not require Hsp70 and Hsp40 for disaggregase activity; Hsp70 and Hsp40 do not stimulate disaggregase activity |
| Y507A | Suppresses toxicity of TDP-43, FUS, and α-syn; Does not require Hsp70 and Hsp40 for disaggregase activity | |
| Y507D | Suppresses toxicity of TDP-43, FUS, and α-syn | |
| Y507V | 3 | Suppresses toxicity of FUS, and α-syn; Does not modify TDP-43 toxicity; Elevated ATPase and disaggregase activity; Does not require Hsp70 and Hsp40 for disaggregase activity |
| Y507C | 3 | Suppresses toxicity of TDP-43, FUS, and α-syn; Enhances EWSR1 toxicity; Elevated ATPase, disaggregase, and unfoldase activity; Does not require Hsp70 and Hsp40 for disaggregase activity |
| N539L/E/D/G | Small domain NBD1 | Suppresses toxicity of FUS |
| N539K | Small domain NBD1 | Suppresses toxicity of TDP-43, FUS, and α-syn; Does not modify EWSR1 toxicity |
*
X = any amino acid except A or P.