Detail
Článek
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

AB. Loveland, E. Svidritskiy, D. Susorov, S. Lee, A. Park, S. Zvornicanin, G. Demo, FB. Gao, AA. Korostelev

. 2022 ; 13 (1) : 2776. [pub] 20220519

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural

Perzistentní odkaz   https://www.medvik.cz/link/bmc22018364

Grantová podpora
R01 NS101986 NINDS NIH HHS - United States
R35 GM127094 NIGMS NIH HHS - United States
R01 GM107465 NIGMS NIH HHS - United States
R37 NS057553 NINDS NIH HHS - United States

Toxic dipeptide-repeat (DPR) proteins are produced from expanded G4C2 repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.

000      
00000naa a2200000 a 4500
001      
bmc22018364
003      
CZ-PrNML
005      
20220804134727.0
007      
ta
008      
220720s2022 xxk f 000 0|eng||
009      
AR
024    7_
$a 10.1038/s41467-022-30418-0 $2 doi
035    __
$a (PubMed)35589706
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxk
100    1_
$a Loveland, Anna B $u RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA $1 https://orcid.org/0000000191727747
245    10
$a Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM / $c AB. Loveland, E. Svidritskiy, D. Susorov, S. Lee, A. Park, S. Zvornicanin, G. Demo, FB. Gao, AA. Korostelev
520    9_
$a Toxic dipeptide-repeat (DPR) proteins are produced from expanded G4C2 repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.
650    12
$a amyotrofická laterální skleróza $x genetika $x metabolismus $7 D000690
650    _2
$a protein C9orf72 $x genetika $x metabolismus $7 D000073885
650    _2
$a elektronová kryomikroskopie $7 D020285
650    _2
$a dipeptidy $x metabolismus $7 D004151
650    12
$a frontotemporální demence $x genetika $x metabolismus $7 D057180
650    _2
$a lidé $7 D006801
650    _2
$a proteiny $x genetika $x metabolismus $7 D011506
650    _2
$a ribozomy $x metabolismus $7 D012270
650    _2
$a transferasy $7 D014166
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
655    _2
$a Research Support, N.I.H., Extramural $7 D052061
700    1_
$a Svidritskiy, Egor $u RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
700    1_
$a Susorov, Denis $u RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
700    1_
$a Lee, Soojin $u Department of Neurology, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
700    1_
$a Park, Alexander $u RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
700    1_
$a Zvornicanin, Sarah $u RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
700    1_
$a Demo, Gabriel $u RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA $u Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic $1 https://orcid.org/0000000254729249
700    1_
$a Gao, Fen-Biao $u Department of Neurology, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA. Fen-Biao.Gao@umassmed.edu $1 https://orcid.org/0000000188735404
700    1_
$a Korostelev, Andrei A $u RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA. Andrei.Korostelev@umassmed.edu $1 https://orcid.org/000000031588717X
773    0_
$w MED00184850 $t Nature communications $x 2041-1723 $g Roč. 13, č. 1 (2022), s. 2776
856    41
$u https://pubmed.ncbi.nlm.nih.gov/35589706 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220720 $b ABA008
991    __
$a 20220804134721 $b ABA008
999    __
$a ok $b bmc $g 1822115 $s 1169607
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2022 $b 13 $c 1 $d 2776 $e 20220519 $i 2041-1723 $m Nature communications $n Nat Commun $x MED00184850
GRA    __
$a R01 NS101986 $p NINDS NIH HHS $2 United States
GRA    __
$a R35 GM127094 $p NIGMS NIH HHS $2 United States
GRA    __
$a R01 GM107465 $p NIGMS NIH HHS $2 United States
GRA    __
$a R37 NS057553 $p NINDS NIH HHS $2 United States
LZP    __
$a Pubmed-20220720

Najít záznam

Citační ukazatele

Možnosti archivace