TY  - JOUR
AU  - Ibanez de Opakua, Alain
AU  - Geraets, James A
AU  - Frieg, Benedikt
AU  - Dienemann, Christian
AU  - Savastano, Adriana
AU  - Rankovic, Marija
AU  - Cima-Omori, Maria-Sol
AU  - Schröder, Gunnar F
AU  - Zweckstetter, Markus
TI  - Molecular interactions of FG nucleoporin repeats at high resolution.
JO  - Nature chemistry
VL  - 14
IS  - 11
SN  - 1755-4330
CY  - London
PB  - Nature Publishing Group
M1  - DZNE-2022-01516
SP  - 1278 - 1285
PY  - 2022
N1  - CC BY: https://creativecommons.org/licenses/by/4.0/
AB  - Proteins that contain repeat phenylalanine-glycine (FG) residues phase separate into oncogenic transcription factor condensates in malignant leukaemias, form the permeability barrier of the nuclear pore complex and mislocalize in neurodegenerative diseases. Insights into the molecular interactions of FG-repeat nucleoporins have, however, remained largely elusive. Using a combination of NMR spectroscopy and cryoelectron microscopy, we have identified uniformly spaced segments of transient β-structure and a stable preformed α-helix recognized by messenger RNA export factors in the FG-repeat domain of human nucleoporin 98 (Nup98). In addition, we have determined at high resolution the molecular organization of reversible FG-FG interactions in amyloid fibrils formed by a highly aggregation-prone segment in Nup98. We have further demonstrated that amyloid-like aggregates of the FG-repeat domain of Nup98 have low stability and are reversible. Our results provide critical insights into the molecular interactions underlying the self-association and phase separation of FG-repeat nucleoporins in physiological and pathological cell activities.
KW  - Humans
KW  - Cryoelectron Microscopy
KW  - Nuclear Pore: chemistry
KW  - Nuclear Pore: metabolism
KW  - Nuclear Pore Complex Proteins: genetics
KW  - Nuclear Pore Complex Proteins: analysis
KW  - Nuclear Pore Complex Proteins: chemistry
KW  - Phenylalanine: chemistry
KW  - Repetitive Sequences, Amino Acid
KW  - Nuclear Pore Complex Proteins (NLM Chemicals)
KW  - Phenylalanine (NLM Chemicals)
KW  - Nup98 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9630130
C6  - pmid:36138110
DO  - DOI:10.1038/s41557-022-01035-7
UR  - https://pub.dzne.de/record/165219
ER  -