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TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase separation is mediated by just a few aromatic residues.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2018 Apr 20; Vol. 293 (16), pp. 6090-6098. Date of Electronic Publication: 2018 Mar 06. - Publication Year :
- 2018
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Abstract
- Eukaryotic cells contain distinct organelles, but not all of these compartments are enclosed by membranes. Some intrinsically disordered proteins mediate membraneless organelle formation through liquid-liquid phase separation (LLPS). LLPS facilitates many biological functions such as regulating RNA stability and ribonucleoprotein assembly, and disruption of LLPS pathways has been implicated in several diseases. Proteins exhibiting LLPS typically have low sequence complexity and specific repeat motifs. These motifs promote multivalent connections with other molecules and the formation of higher-order oligomers, and their removal usually prevents LLPS. The intrinsically disordered C-terminal domain of TAR DNA-binding protein 43 (TDP-43), a protein involved in motor neuron disease and dementia lacks a dominant LLPS motif, however, and how this domain forms condensates is unclear. Using extensive mutagenesis of TDP-43, we demonstrate here that three tryptophan residues and, to a lesser extent, four other aromatic residues are most important for TDP-43 to undergo LLPS. Our results also suggested that only a few residues may be required for TDP-43 LLPS because the α-helical segment (spanning ∼20 residues) in the middle part of the C-terminal domain tends to self-assemble, reducing the number of motifs required for forming a multivalent connection. Our results indicating that a self-associating α-helical element with a few key residues regulates condensate formation highlight a different type of LLPS involving intrinsically disordered regions. The C-terminal domain of TDP-43 contains ∼50 disease-related mutations, with no clear physicochemical link between them. We propose that they may disrupt LLPS indirectly by interfering with the key residues identified here.<br /> (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Amino Acids, Aromatic chemistry
Amino Acids, Aromatic genetics
Amyotrophic Lateral Sclerosis genetics
Amyotrophic Lateral Sclerosis metabolism
DNA-Binding Proteins chemistry
DNA-Binding Proteins genetics
Dementia genetics
Dementia metabolism
Humans
Intrinsically Disordered Proteins chemistry
Intrinsically Disordered Proteins genetics
Motor Neuron Disease genetics
Motor Neuron Disease metabolism
Mutation
Nuclear Magnetic Resonance, Biomolecular
Phase Transition
Protein Domains
Tryptophan chemistry
Tryptophan metabolism
Amino Acids, Aromatic metabolism
DNA-Binding Proteins metabolism
Intrinsically Disordered Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 293
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29511089
- Full Text :
- https://doi.org/10.1074/jbc.AC117.001037