Abstract
RNA-binding proteins TDP-43 and FUS play essential roles in pre-mRNA splicing, localization, granule formation and other aspects of RNA metabolism. Both proteins are implicated in neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite their apparent similarities, each protein has unique structural characteristics. Here we present the current structural understanding of RNA-binding and self-association mechanisms. Both globular and intrinsically disordered domains contribute to RNA binding, each with different specificities, affinities and kinetics. Self-associating Prion-like domains in each protein form multivalent interactions and labile cross-β structures. These interactions are modulated by distinctive additional domains including a globular oligomerization domain in TDP-43 and synergistic interactions with intrinsically disordered Arginine-Glycine rich domains in FUS. These insights contribute to a better understanding of native biological functions of TDP-43 and FUS and potential molecular pathways in neurodegenerative diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 134-142 |
| Number of pages | 9 |
| Journal | Current Opinion in Structural Biology |
| Volume | 59 |
| DOIs | |
| Publication status | Published - 1 Dec 2019 |
Cite this
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TDP-43 and FUS–structural insights into RNA recognition and self-association. / Loughlin, Fionna E; Wilce, Jacqueline A.
In: Current Opinion in Structural Biology, Vol. 59, 01.12.2019, p. 134-142.Research output: Contribution to journal › Review Article › Research › peer-review
TY - JOUR
T1 - TDP-43 and FUS–structural insights into RNA recognition and self-association
AU - Loughlin, Fionna E
AU - Wilce, Jacqueline A
PY - 2019/12/1
Y1 - 2019/12/1
N2 - RNA-binding proteins TDP-43 and FUS play essential roles in pre-mRNA splicing, localization, granule formation and other aspects of RNA metabolism. Both proteins are implicated in neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite their apparent similarities, each protein has unique structural characteristics. Here we present the current structural understanding of RNA-binding and self-association mechanisms. Both globular and intrinsically disordered domains contribute to RNA binding, each with different specificities, affinities and kinetics. Self-associating Prion-like domains in each protein form multivalent interactions and labile cross-β structures. These interactions are modulated by distinctive additional domains including a globular oligomerization domain in TDP-43 and synergistic interactions with intrinsically disordered Arginine-Glycine rich domains in FUS. These insights contribute to a better understanding of native biological functions of TDP-43 and FUS and potential molecular pathways in neurodegenerative diseases.
AB - RNA-binding proteins TDP-43 and FUS play essential roles in pre-mRNA splicing, localization, granule formation and other aspects of RNA metabolism. Both proteins are implicated in neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite their apparent similarities, each protein has unique structural characteristics. Here we present the current structural understanding of RNA-binding and self-association mechanisms. Both globular and intrinsically disordered domains contribute to RNA binding, each with different specificities, affinities and kinetics. Self-associating Prion-like domains in each protein form multivalent interactions and labile cross-β structures. These interactions are modulated by distinctive additional domains including a globular oligomerization domain in TDP-43 and synergistic interactions with intrinsically disordered Arginine-Glycine rich domains in FUS. These insights contribute to a better understanding of native biological functions of TDP-43 and FUS and potential molecular pathways in neurodegenerative diseases.
UR - http://www.scopus.com/inward/record.url?scp=85071400152&partnerID=8YFLogxK
U2 - 10.1016/j.sbi.2019.07.012
DO - 10.1016/j.sbi.2019.07.012
M3 - Review Article
VL - 59
SP - 134
EP - 142
JO - Current Opinion in Structural Biology
JF - Current Opinion in Structural Biology
SN - 0959-440X
ER -