Title:
Hidden Biological Function of Low-complexity Sequences in RNA Granule Formation

Masato Kato, Ph.D.
Associate Professor　
Department of Biochemistry
University of Texas Southwestern Medical Center

Abstract:
Low-complexity (LC) sequences are disordered regions/domains in proteins with little diversity in their amino acid composition and have been believed to perform important biological roles by unknown mechanisms. By accident, we have discovered that purified liquid samples of the LC domains of RNA-binding proteins, such as FUS, hnRNPA2 and TDP-43, made the transition into a gel-like phase in a concentration-dependent manner^1,2. The hydrogels are composed of morphologically uniform polymers endowed with a signature cross-β structure of amyloid fibers. Unlike pathogenic amyloid fibers that are virtually irreversible, our polymeric fibers are reversible. The hydrogels have capability to capture LC domains of RNA granule proteins. The underlying mechanism for the hydrogel retention was shown to be co-polymerization of the test LC domain and the LC domain forming the hydrogel into a single polymeric fiber. The C-terminal domain (CTD) of RNA polymerase II and arginine/serine-rich (RS) domains of splicing factors also bind to the hydrogels, yet these interactions are reversible by phosphorylation of CTD and RS domains by their respective kinases^{3, 4}. The outcome of these studies has led to a conceptual framework hypothesizing the structural underpinnings of how dynamic puncta, including RNA granules, transcription factories and nuclear speckles, form in eukaryotic cells.

References:
1. Kato et al., Cell-Free Formation of RNA Granules: Low Complexity Sequence Domains Form Dynamic Fibers Within Hydrogels, Cell 149,753-767 (2012)
2. Han et al., Cell-Free Formation of RNA Granules: Bound RNAs Identify Features and Components of Cellular Assemblies, Cell 149, 768-779 (2012)
3. Kwon and Kato et al., Phosphorylation-regulated Binding of RNA Polymerase II to Fibrous Polymers of Low-Complexity Domains, Cell 155, 1049 (2013)
4. Kwon et al., Poly-dipeptides encoded by the C9ORF72 repeats bind nucleoli, impede RNA biogenesis and kill cells, Science, 345, 1139-1145 (2014)