New Family Members of FG Repeat Proteins and Their Unexplored Roles During Phase Separation

Abstract

The condensation and compartmentalization of biomacromolecules in the cell are driven by the process of phase separation. The main effectors of phase separation are intrinsically disordered proteins, which include proteins with a phenylalanine-glycine (FG) repeat domain. Our understanding of the biological function of FG repeat proteins during phase separation has been mainly derived from recent research on a member of the nuclear pore complex proteins, nucleoporins containing FG repeat domain (FG-NUPs). FG-NUPs form meshwork structures by inter- and intra-molecular FG domain interactions, which confine the nucleo-cytoplasmic exchange. Whereas FG-NUPs localize in the nuclear membrane, other FG repeat proteins reside in the cytoplasm and the nucleoplasm, and the biological function of the FG repeat domain of these proteins is not well described. In the present review, we list the FG repeat proteins that are known to phase separate in the cell, and review their biological functions. We extract the unraveled features of FG repeat proteins as an activator of barrier formation and homotypic cell-cell interactions. Understanding the regulatory mechanisms of FG repeat proteins will provide a potential delivery tool for therapeutic reagents.

Two structural switches in HIV-1 capsid regulate capsid curvature and host factor binding

“…A second binding site within the CANTD specifically binds phenylalanine-glycine (FG) motifs (22)(23)(24). FG-repeat-containing host factors are diverse in their cellular distribution and function (25) and include: Nup153, a nuclear pore complex component; Sec24c, a member of the COPII complex implicated in intracellular vesicle trafficking; and the nuclear-localised CPSF6 (23,24). All three proteins insert an FG motif into a pocket between helices 3 and 4 of the CANTD, while residues proximal to the FG repeat bind to CA residues in a cleft formed between the CANTD and the CACTD of the neighbouring CA in the hexamer.…”

The Influenza A Virus Replication Cycle: A Comprehensive Review

“…Nups enriched in hydrophobic FG repeats line the NPC central pore, forming a hydrogel plug only permeable to soluble proteins lighter than 40–60 kDa [ 159 , 161 ]. Any soluble proteins heavier than this require a nuclear transport receptor to pass through the NPC [ 162 ]; for vRNPs, this receptor is importin β1 [ 14 , 25 , 163 , 164 ].…”

“…Binding to the NLS releases the importin β-binding (IBB) domain of importin α, thus recruiting importin β to the complex [ 159 ]. Importin β1 interacts with the FG repeats lining the NPC central pore, allowing it (and by extension importin α and the vRNPs) to slide through the NPC and enter the nucleus [ 162 ]. The nascently imported importin β1 binds GTP-bound Ran (RanGTP), dissociating it and thus releasing the vRNP-importin α complex into the nucleus for viral transcription and replication [ 16 , 166 ]; whether importin α remains associated with vRNPs post-import is unknown [ 20 ].…”

Molecular interactions of FG nucleoporin repeats at high resolution

“…In addition, they are involved in cancer-associated biomolecular condensates, the so-called oncogenic transcription factor condensates 9 – 12 . FG-repeat proteins are also present in several other membraneless organelles 3 . Increasing evidence further links cellular mislocalization of FG-repeat-containing nucleoporins to pathological protein misfolding and aggregation in neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis and frontotemporal dementia 13 , 14 .…”