TDP-43 forms a functional dimer interface upon UG-rich RNA
binding leading to aberrant CFTR exon 9 splicing

a 2017

TDP-43 forms a functional dimer interface upon UG-rich RNA binding leading to aberrant CFTR exon 9 splicing

ZLOBINA, Maria; Christelle BEAUMONT a Peter LUKAVSKY

Základní údaje

Originální název

TDP-43 forms a functional dimer interface upon UG-rich RNA binding leading to aberrant CFTR exon 9 splicing

Autoři

ZLOBINA, Maria ; Christelle BEAUMONT a Peter LUKAVSKY

Vydání

2017

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.530

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/17:00113362

Organizační jednotka

Středoevropský technologický institut

ISSN

UT WoS

000409918901064

Klíčová slova anglicky

TDP43; UGrich RNA

Štítky

rivok

Příznaky

Mezinárodní význam

Změněno: 26. 3. 2020 21:49, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

Alternative premRNA splicing plays a key role in creating the vast number of gene products underlying our complex organism. Processing of premRNAs is tightly regulated and imbalances can change the outcome of gene expression often leading to disease. TAR DNAbinding protein (TDP43) inhibits splicing of exon 9 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is associated with severe forms of cystic fibrosis. Mutations in the 3’ splice site (3’ss) of CFTR exon 9 causing extension of a UGrich region and polypyrimidine tract shortening, create a high affinity binding site for TDP43. Upon RNA binding, TDP43 recruits hnRNPA1 and thus formed complex prevents the recognition of the 3’ss of exon 9 by the spliceosomal machinery causing exon 9 skipping and subsequent production of a nonfunctional CFTR protein. Although RNA recognition and binding by TDP43 alone and in complex with other hnRNPs has numerous functional implications, molecular details of such interactions remained elusive. Our structural studies combined with biophysical approaches reveal that two copies of TDP43 create a new proteinprotein interface with a salt bridge upon binding to the extended UGrich sequence. Sitedirected mutagenesis of amino acids involved in salt bridge formation reveals the functional significance of the proteinprotein interface. Unexpectedly, mutations at the interaction site of the two TDP43 copies reduce exon 9 skipping almost to the same extent as completely abolishing UGrich RNA binding. Furthermore, this complex recruits two copies of hnRNP A1 to the 3’ss which blocks access of the canonical factor U2AF35 while U2AF65 binding is weakened because of polypyrimidine tract shortening. Thus TDP43 and hnRNP A1 form a network of functional RNAprotein and proteinprotein interactions which competes for the formation of the canonical splicing complex thereby driving CFTR exon 9 skipping

Návaznosti

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

Citovat

ZLOBINA, Maria; Christelle BEAUMONT a Peter LUKAVSKY. TDP-43 forms a functional dimer interface upon UG-rich RNA binding leading to aberrant CFTR exon 9 splicing. 2017. ISSN 1742-464X.

@proceedings{1639677,
   author = {Zlobina, Maria and Beaumont, Christelle and Lukavsky, Peter},
   keywords = {TDP43; UGrich RNA},
   language = {eng},
   title = {TDP-43 forms a functional dimer interface upon UG-rich RNA binding leading to aberrant CFTR exon 9 splicing},
   url = {https://2017.febscongress.org/abstract_preview.aspx?idAbstractEnc=4424170096100095091424170},
   year = {2017}
}

TY  - CONF
ID  - 1639677
AU  - Zlobina, Maria - Beaumont, Christelle - Lukavsky, Peter
PY  - 2017
TI  - TDP-43 forms a functional dimer interface upon UG-rich RNA binding leading to aberrant CFTR exon 9 splicing
KW  - TDP43
KW  - UGrich RNA
UR  - https://2017.febscongress.org/abstract_preview.aspx?idAbstractEnc=4424170096100095091424170
L2  - https://2017.febscongress.org/abstract_preview.aspx?idAbstractEnc=4424170096100095091424170
N2  - Alternative premRNA splicing plays a key role in creating the vast number of gene products underlying our complex organism. Processing of premRNAs is tightly regulated and imbalances can change the outcome of gene expression often leading to disease. TAR DNAbinding protein (TDP43) inhibits splicing of exon 9 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is associated with severe forms of cystic fibrosis. Mutations in the 3’ splice site (3’ss) of CFTR exon 9 causing extension of a UGrich region and polypyrimidine tract shortening, create a high affinity binding site for TDP43. Upon RNA binding, TDP43 recruits hnRNPA1 and thus formed complex prevents the recognition of the 3’ss of exon 9 by the spliceosomal machinery causing exon 9 skipping and subsequent production of a nonfunctional CFTR protein. Although RNA recognition and binding by TDP43 alone and in complex with other hnRNPs has numerous functional implications, molecular details of such interactions remained elusive. Our structural studies combined with biophysical approaches reveal that two copies of TDP43 create a new proteinprotein interface with a salt bridge upon binding to the extended UGrich sequence. Sitedirected mutagenesis of amino acids involved in salt bridge formation reveals the functional significance of the proteinprotein interface. Unexpectedly, mutations at the interaction site of the two TDP43 copies reduce exon 9 skipping almost to the same extent as completely abolishing UGrich RNA binding. Furthermore, this complex recruits two copies of hnRNP A1 to the 3’ss which blocks access of the canonical factor U2AF35 while U2AF65 binding is weakened because of polypyrimidine tract shortening. Thus TDP43 and hnRNP A1 form a network of functional RNAprotein and proteinprotein interactions which competes for the formation of the canonical splicing complex thereby driving CFTR exon 9 skipping
ER  -

ZLOBINA, Maria; Christelle BEAUMONT a Peter LUKAVSKY. \textit{TDP-43 forms a functional dimer interface upon UG-rich RNA binding leading to aberrant CFTR exon 9 splicing}. 2017. ISSN~1742-464X.

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