Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F13%3A00070459" target="_blank" >RIV/00216224:14740/13:00070459 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.nature.com/nsmb/journal/v20/n12/pdf/nsmb.2698.pdf" target="_blank" >http://www.nature.com/nsmb/journal/v20/n12/pdf/nsmb.2698.pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/nsmb.2698" target="_blank" >10.1038/nsmb.2698</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43

Popis výsledku v původním jazyce

TDP-43 encodes an alternative-splicing regulator with tandem RNA-recognition motifs (RRMs). The protein regulates cystic fibrosis transmembrane regulator ( CFTR ) exon 9 splicing through binding to long UG-rich RNA sequences and is found in cytoplasmic inclusions of several neurodegenerative diseases. We solved the solution structure of the TDP-43 RRMs in complex with UG-rich RNA. Ten nucleotides are bound by both RRMs, and six are recognized sequence specifically. Among these, a central G interacts with both RRMs and stabilizes a new tandem RRM arrangement. Mutations that eliminate recognition of this key nucleotide or crucial inter-RRM interactions disrupt RNA binding and TDP-43?dependent splicing regulation. In contrast, point mutations that affectbase-specific recognition in either RRM have weaker effects. Our findings reveal not only how TDP-43 recognizes UG repeats but also how RNA binding?dependent inter-RRM interactions are crucial for TDP-43 function.

Název v anglickém jazyce

Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43

Popis výsledku anglicky

TDP-43 encodes an alternative-splicing regulator with tandem RNA-recognition motifs (RRMs). The protein regulates cystic fibrosis transmembrane regulator ( CFTR ) exon 9 splicing through binding to long UG-rich RNA sequences and is found in cytoplasmic inclusions of several neurodegenerative diseases. We solved the solution structure of the TDP-43 RRMs in complex with UG-rich RNA. Ten nucleotides are bound by both RRMs, and six are recognized sequence specifically. Among these, a central G interacts with both RRMs and stabilizes a new tandem RRM arrangement. Mutations that eliminate recognition of this key nucleotide or crucial inter-RRM interactions disrupt RNA binding and TDP-43?dependent splicing regulation. In contrast, point mutations that affectbase-specific recognition in either RRM have weaker effects. Our findings reveal not only how TDP-43 recognizes UG repeats but also how RNA binding?dependent inter-RRM interactions are crucial for TDP-43 function.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EB - Genetika a molekulární biologie

OECD FORD obor

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Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2013

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

NATURE STRUCTURAL & MOLECULAR BIOLOGY

ISSN

1545-9993

e-ISSN

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Svazek periodika

20

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

7

Strana od-do

1443-1449

Kód UT WoS článku

000328007600017

EID výsledku v databázi Scopus

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