ALS-Linked Mutations Affect UBQLN2 Oligomerization and Phase Separation in a Position- and Amino Acid-Dependent Manner
| Autor: | Michael S. Cosgrove, Carlos A. Castañeda, Yongna Lei, Brian Martyniak, Ashley J. Canning, Heidi Hehnly, Erica G. Colicino, Thuy P. Dao |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences biology Chemistry 030302 biochemistry & molecular biology Mutant Nuclear magnetic resonance spectroscopy medicine.disease UBQLN2 Amino acid 03 medical and health sciences Ubiquilin-2 Stress granule Ubiquitin Structural Biology biology.protein Biophysics medicine Amyotrophic lateral sclerosis Molecular Biology 030304 developmental biology |
| Zdroj: | Structure. 27:937-951.e5 |
| ISSN: | 0969-2126 |
| DOI: | 10.1016/j.str.2019.03.012 |
| Popis: | Summary Proteasomal shuttle factor UBQLN2 is recruited to stress granules and undergoes liquid-liquid phase separation (LLPS) into protein-containing droplets. Mutations to UBQLN2 have recently been shown to cause dominant X-linked inheritance of amyotrophic lateral sclerosis (ALS) and ALS/dementia. Interestingly, most of these UBQLN2 mutations reside in its proline-rich (Pxx) region, an important modulator of LLPS. Here, we demonstrated that ALS-linked Pxx mutations differentially affect UBQLN2 LLPS, depending on both amino acid substitution and sequence position. Using size-exclusion chromatography, analytical ultracentrifugation, microscopy, and NMR spectroscopy, we determined that those Pxx mutants that enhanced UBQLN2 oligomerization decreased saturation concentrations needed for LLPS and promoted solid-like and viscoelastic morphological changes to UBQLN2 liquid assemblies. Ubiquitin disassembled all LLPS-induced mutant UBQLN2 aggregates. We postulate that the changes in physical properties caused by ALS-linked Pxx mutations modify UBQLN2 behavior in vivo, possibly contributing to aberrant stress granule morphology and dynamics, leading to formation of inclusions, pathological characteristics of ALS. |
| Databáze: | OpenAIRE |
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