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

J 2013

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

LUKAVSKY, Peter, Dalia DAUJOTYTE, James R TOLLERVEY, Jernej ULE, Cristiana STUANI et. al.

Basic information

Original name

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

Authors

LUKAVSKY, Peter (40 Austria, guarantor, belonging to the institution), Dalia DAUJOTYTE (40 Austria), James R TOLLERVEY (840 United States of America), Jernej ULE (826 United Kingdom of Great Britain and Northern Ireland), Cristiana STUANI (380 Italy), Emanuele BURATTI (380 Italy), Francisco E BARALLE (380 Italy), Fred F DAMBERGER (756 Switzerland) and H-T Allain FRÉDÉRIC (756 Switzerland)

Edition

NATURE STRUCTURAL & MOLECULAR BIOLOGY, New York, NATURE PUBLISHING GROUP, 2013, 1545-9993

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

Genetics and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 11.633

RIV identification code

RIV/00216224:14740/13:00070459

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1038/nsmb.2698

UT WoS

000328007600017

Keywords in English

TDP-43; RNA recognition; RRM; CFTR

Abstract

V originále

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 affect base-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.

Links

ED1.1.00/02.0068, research and development project

Name: CEITEC - central european institute of technology

EE2.3.20.0042, research and development project

Name: Internacionalizace programu Strukturní biologie s důrazem na rozvoj nových směrů výzkumu

Citovat

LUKAVSKY, Peter, Dalia DAUJOTYTE, James R TOLLERVEY, Jernej ULE, Cristiana STUANI, Emanuele BURATTI, Francisco E BARALLE, Fred F DAMBERGER and H-T Allain FRÉDÉRIC. Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43. NATURE STRUCTURAL & MOLECULAR BIOLOGY. New York: NATURE PUBLISHING GROUP, 2013, vol. 20, No 12, p. 1443-1449. ISSN 1545-9993. Available from: https://dx.doi.org/10.1038/nsmb.2698.

@article{1136046,
   author = {Lukavsky, Peter and Daujotyte, Dalia and Tollervey, James R and Ule, Jernej and Stuani, Cristiana and Buratti, Emanuele and Baralle, Francisco E and Damberger, Fred F and Frédéric, HandT Allain},
   article_location = {New York},
   article_number = {12},
   doi = {http://dx.doi.org/10.1038/nsmb.2698},
   keywords = {TDP-43; RNA recognition; RRM; CFTR},
   language = {eng},
   issn = {1545-9993},
   journal = {NATURE STRUCTURAL & MOLECULAR BIOLOGY},
   title = {Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43},
   url = {http://www.nature.com/nsmb/journal/v20/n12/pdf/nsmb.2698.pdf},
   volume = {20},
   year = {2013}
}

TY  - JOUR
ID  - 1136046
AU  - Lukavsky, Peter - Daujotyte, Dalia - Tollervey, James R - Ule, Jernej - Stuani, Cristiana - Buratti, Emanuele - Baralle, Francisco E - Damberger, Fred F - Frédéric, H-T Allain
PY  - 2013
TI  - Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43
JF  - NATURE STRUCTURAL & MOLECULAR BIOLOGY
VL  - 20
IS  - 12
SP  - 1443-1449
EP  - 1443-1449
PB  - NATURE PUBLISHING GROUP
SN  - 15459993
KW  - TDP-43
KW  - RNA recognition
KW  - RRM
KW  - CFTR
UR  - http://www.nature.com/nsmb/journal/v20/n12/pdf/nsmb.2698.pdf
L2  - http://www.nature.com/nsmb/journal/v20/n12/pdf/nsmb.2698.pdf
N2  - 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 affect base-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.
ER  -

LUKAVSKY, Peter, Dalia DAUJOTYTE, James R TOLLERVEY, Jernej ULE, Cristiana STUANI, Emanuele BURATTI, Francisco E BARALLE, Fred F DAMBERGER and H-T Allain FRÉDÉRIC. Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43. \textit{NATURE STRUCTURAL \&{} MOLECULAR BIOLOGY}. New York: NATURE PUBLISHING GROUP, 2013, vol.~20, No~12, p.~1443-1449. ISSN~1545-9993. Available from: https://dx.doi.org/10.1038/nsmb.2698.

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