Personal tools
You are here: Home Administration Chemistry & Biochemistry Department Events 2019 February Biochemistry Seminar: Nicolas Lux Fawzi, "Functional and pathological RNA-binding protein phase separation with atomistic detail"

Biochemistry Seminar: Nicolas Lux Fawzi, "Functional and pathological RNA-binding protein phase separation with atomistic detail"

Nicolas Lux Fawzi, Assistant Professor of Medical Science, Department of Molecular Pharmacology, Physiology & Biotechnology, Brown University, RI, "Functional and pathological RNA-binding protein phase separation with atomistic detail"
When Feb 13, 2019
from 12:00 PM to 01:00 PM
Where CUNY ASRC Main Auditorium
Contact Name
Contact Phone 212-650-8803
Add event to calendar vCal
iCal

ABSTRACT

The contacts that stabilize the liquid-liquid phase separated forms of RNA-binding proteins remains poorly understood in part because they are difficult to directly visualize. Recent structures of amyloid-like fibrillar assemblies formed by the low complexity domains (LC) of FUS, TDP-43, and hnRNPA2 hint that beta-sheet contacts may stabilize phase separated assemblies. On the other hand, we have previously shown that LC domains remain predominantly disordered, yet the structural details of the contacts remain unknown. First, using a combination of NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that non-specific interactions involving all residue types underlie LLPS of FUS LC. By directly probing the condensed phase of FUS LC, we find no evidence that FUS LC in the liquid phase takes on conformations with traditional secondary structure elements but rather maintains conformational heterogeneity. We find evidence that glutamine amino acid hydrogen bonding and glutamine/tyrosine hydrophobic interactions, not tyrosine π-stacking, are the primary interactions stabilizing liquid-liquid phase separation of FUS LC. Second, we previously showed that TDP-43 C-terminal domain contains an alpha-helical segment that cooperates with the surrounding LC regions to mediate phase separation. Now, we show that by mutating a single position to stabilize helicity, we can increase the helical content of the sequence and drive phase separation in vitro and in cells, alter in cell condensate material properties, and enhance TDP-43 splicing function.

More information about this event…