+
Open data
-
Basic information
Entry | ![]() | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | HnRNPA2 D290V LCD PM1 | |||||||||
![]() | ||||||||||
![]() |
| |||||||||
![]() | Amyloid / PROTEIN FIBRIL | |||||||||
Function / homology | ![]() : / miRNA transport / positive regulation of telomere maintenance via telomere lengthening / RNA transport / G-quadruplex DNA unwinding / primary miRNA processing / single-stranded telomeric DNA binding / N6-methyladenosine-containing RNA reader activity / G-rich strand telomeric DNA binding / miRNA binding ...: / miRNA transport / positive regulation of telomere maintenance via telomere lengthening / RNA transport / G-quadruplex DNA unwinding / primary miRNA processing / single-stranded telomeric DNA binding / N6-methyladenosine-containing RNA reader activity / G-rich strand telomeric DNA binding / miRNA binding / negative regulation of mRNA splicing, via spliceosome / Processing of Capped Intron-Containing Pre-mRNA / mRNA transport / mRNA export from nucleus / Cajal body / pre-mRNA intronic binding / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / catalytic step 2 spliceosome / mRNA Splicing - Major Pathway / molecular condensate scaffold activity / mRNA 3'-UTR binding / spliceosomal complex / nuclear matrix / mRNA splicing, via spliceosome / mRNA processing / chromosome, telomeric region / ribonucleoprotein complex / negative regulation of transcription by RNA polymerase II / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / membrane / nucleus / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
![]() | Eisenberg DS / Lu J / Ge P / Boyer DR | |||||||||
Funding support | ![]()
| |||||||||
![]() | ![]() Title: Cryo-EM structures of the D290V mutant of the hnRNPA2 low-complexity domain suggests how D290V affects phase separation and aggregation. Authors: Jiahui Lu / Peng Ge / Michael R Sawaya / Michael P Hughes / David R Boyer / Qin Cao / Romany Abskharon / Duilio Cascio / Einav Tayeb-Fligelman / David S Eisenberg / ![]() ![]() Abstract: Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, ...Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, D290V, is implicated in multisystem proteinopathy known to afflict two families, mainly with myopathy and Paget's disease of bone. Here, we investigate this mutant form of hnRNPA2 by determining cryo-EM structures of the recombinant D290V low complexity domain. We find that the mutant form of hnRNPA2 differs from the WT fibrils in four ways. In contrast to the WT fibrils, the PY-nuclear localization signals in the fibril cores of all three mutant polymorphs are less accessible to chaperones. Also, the mutant fibrils are more stable than WT fibrils as judged by phase separation, thermal stability, and energetic calculations. Similar to other pathogenic amyloids, the mutant fibrils are polymorphic. Thus, these structures offer evidence to explain how a D-to-V missense mutation diverts the assembly of reversible, functional amyloid-like fibrils into the assembly of pathogenic amyloid, and may shed light on analogous conversions occurring in other ribonucleoproteins that lead to neurological diseases such as amyotrophic lateral sclerosis and frontotemporal dementia. | |||||||||
History |
|
-
Structure visualization
Supplemental images |
---|
-
Downloads & links
-EMDB archive
Map data | ![]() | 105.4 MB | ![]() | |
---|---|---|---|---|
Header (meta data) | ![]() ![]() | 13.7 KB 13.7 KB | Display Display | ![]() |
Images | ![]() | 49 KB | ||
Filedesc metadata | ![]() | 5.1 KB | ||
Others | ![]() ![]() | 19.7 MB 19.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8du2MC ![]() 8duwC ![]() 8ec7C M: atomic model generated by this map C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
EMDB pages | ![]() ![]() |
---|---|
Related items in Molecule of the Month |
-
Map
File | ![]() | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Voxel size | X=Y=Z: 1.078 Å | ||||||||||||||||||||
Density |
| ||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Half map: #2
File | emd_27713_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: #1
File | emd_27713_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-
Sample components
-Entire : Fibrils of hnRNPA2 D290V LCD PM1
Entire | Name: Fibrils of hnRNPA2 D290V LCD PM1 |
---|---|
Components |
|
-Supramolecule #1: Fibrils of hnRNPA2 D290V LCD PM1
Supramolecule | Name: Fibrils of hnRNPA2 D290V LCD PM1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
---|---|
Source (natural) | Organism: ![]() |
-Macromolecule #1: Heterogeneous nuclear ribonucleoproteins A2/B1
Macromolecule | Name: Heterogeneous nuclear ribonucleoproteins A2/B1 / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 15.391775 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MQEVQSSRSG RGGNFGFGDS RGGGGNFGPG PGSNFRGGSD GYGSGRGFGD GYNGYGGGPG GGNFGGSPGY GGGRGGYGGG GPGYGNQGG GYGGGYDNYG GGNYGSGNYN VFGNYNQQPS NYGPMKSGNF GGSRNMGGPY GGGNYGPGGS GGSGGYGGRS R Y UniProtKB: Heterogeneous nuclear ribonucleoproteins A2/B1 |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
![]() | helical reconstruction |
Aggregation state | filament |
-
Sample preparation
Buffer | pH: 7.4 |
---|---|
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 36.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
-
Image processing
Final reconstruction | Applied symmetry - Helical parameters - Δz: 2.45 Å Applied symmetry - Helical parameters - Δ&Phi: 179.63 ° Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric) Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 5675 |
---|---|
Startup model | Type of model: OTHER / Details: Gaussian blob |
Final angle assignment | Type: NOT APPLICABLE |