Journal
STRUCTURE
Volume 27, Issue 6, Pages 937-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2019.03.012
Keywords
-
Funding
- ALS Association [17-IIP-369, 18-IIP-400]
- National Science Foundation (CAREER award) [1750462]
- NIH [R00 GM107355, 2R01CA140522]
- DOD [PC160083]
- Carol Baldwin Foundation for Central New York
- NIH shared instrumentation grant [1S10OD012254]
- NSF MRI grant [1531757]
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1531757] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1750462] Funding Source: National Science Foundation
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available