A peptide motif in Raver1 mediates splicing repression by interaction with the PTB RRM2 domain

Alexis P. Rideau; Clare Gooding; Peter J. Simpson; Tom P. Monie; Mike Lorenz; Stefan Hüttelmaier; Robert H. Singer; Stephen Matthews; Stephen Curry; Christopher W.J. Smith

doi:10.1038/nsmb1137

A peptide motif in Raver1 mediates splicing repression by interaction with the PTB RRM2 domain

Alexis P. Rideau, Clare Gooding, Peter J. Simpson, Tom P. Monie, Mike Lorenz, Stefan Hüttelmaier, Robert H. Singer, Stephen Matthews, Stephen Curry, Christopher W.J. Smith

Cell Biology

Research output: Contribution to journal › Article › peer-review

82 Scopus citations

Abstract

Polypyrimidine tract-binding protein (PTB) is a regulatory splicing repressor. Raver1 acts as a PTB corepressor for splicing of α-tropomyosin (Tpm1) exon 3. Here we define a minimal region of Raver1 that acts as a repressor domain when recruited to RNA. A conserved [S/G][I/L]LGxxP motif is essential for splicing repressor activity and sufficient for interaction with PTB. An adjacent proline-rich region is also essential for repressor activity but not for PTB interaction. NMR analysis shows that LLGxxP peptides interact with a hydrophobic groove on the dorsal surface of the RRM2 domain of PTB, which constitutes part of the minimal repressor region of PTB. The requirement for the PTB-Raver1 interaction that we have characterized may serve to bring the additional repressor regions of both proteins into a configuration that allows them to synergistically effect exon skipping.

Original language	English (US)
Pages (from-to)	839-848
Number of pages	10
Journal	Nature Structural and Molecular Biology
Volume	13
Issue number	9
DOIs	https://doi.org/10.1038/nsmb1137
State	Published - Sep 2006

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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title = "A peptide motif in Raver1 mediates splicing repression by interaction with the PTB RRM2 domain",

abstract = "Polypyrimidine tract-binding protein (PTB) is a regulatory splicing repressor. Raver1 acts as a PTB corepressor for splicing of α-tropomyosin (Tpm1) exon 3. Here we define a minimal region of Raver1 that acts as a repressor domain when recruited to RNA. A conserved [S/G][I/L]LGxxP motif is essential for splicing repressor activity and sufficient for interaction with PTB. An adjacent proline-rich region is also essential for repressor activity but not for PTB interaction. NMR analysis shows that LLGxxP peptides interact with a hydrophobic groove on the dorsal surface of the RRM2 domain of PTB, which constitutes part of the minimal repressor region of PTB. The requirement for the PTB-Raver1 interaction that we have characterized may serve to bring the additional repressor regions of both proteins into a configuration that allows them to synergistically effect exon skipping.",

author = "Rideau, {Alexis P.} and Clare Gooding and Simpson, {Peter J.} and Monie, {Tom P.} and Mike Lorenz and Stefan H{\"u}ttelmaier and Singer, {Robert H.} and Stephen Matthews and Stephen Curry and Smith, {Christopher W.J.}",

note = "Funding Information: We thank J. Valc{\'a}rcel for helpful comments on the manuscript, B. Jockusch for Raver1 monoclonal antibodies and I. Moss, of the Advanced Biotechnology Centre, Imperial College London, for technical advice and for preparation of the peptides. This work was funded by Wellcome Trust program grant 059879 to C.W.J.S. A.P.R. was supported by a Wellcome Trust Prize studentship. S.M. and S.C. are also indebted to the Wellcome Trust for grant support (078209). S.H. and M.L. were supported by US National Institutes of Health grant AR 41480 to R.H.S.",

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AU - Rideau, Alexis P.

AU - Gooding, Clare

AU - Simpson, Peter J.

AU - Monie, Tom P.

AU - Lorenz, Mike

AU - Hüttelmaier, Stefan

AU - Singer, Robert H.

AU - Matthews, Stephen

AU - Curry, Stephen

AU - Smith, Christopher W.J.

N1 - Funding Information: We thank J. Valcárcel for helpful comments on the manuscript, B. Jockusch for Raver1 monoclonal antibodies and I. Moss, of the Advanced Biotechnology Centre, Imperial College London, for technical advice and for preparation of the peptides. This work was funded by Wellcome Trust program grant 059879 to C.W.J.S. A.P.R. was supported by a Wellcome Trust Prize studentship. S.M. and S.C. are also indebted to the Wellcome Trust for grant support (078209). S.H. and M.L. were supported by US National Institutes of Health grant AR 41480 to R.H.S.

PY - 2006/9

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N2 - Polypyrimidine tract-binding protein (PTB) is a regulatory splicing repressor. Raver1 acts as a PTB corepressor for splicing of α-tropomyosin (Tpm1) exon 3. Here we define a minimal region of Raver1 that acts as a repressor domain when recruited to RNA. A conserved [S/G][I/L]LGxxP motif is essential for splicing repressor activity and sufficient for interaction with PTB. An adjacent proline-rich region is also essential for repressor activity but not for PTB interaction. NMR analysis shows that LLGxxP peptides interact with a hydrophobic groove on the dorsal surface of the RRM2 domain of PTB, which constitutes part of the minimal repressor region of PTB. The requirement for the PTB-Raver1 interaction that we have characterized may serve to bring the additional repressor regions of both proteins into a configuration that allows them to synergistically effect exon skipping.

AB - Polypyrimidine tract-binding protein (PTB) is a regulatory splicing repressor. Raver1 acts as a PTB corepressor for splicing of α-tropomyosin (Tpm1) exon 3. Here we define a minimal region of Raver1 that acts as a repressor domain when recruited to RNA. A conserved [S/G][I/L]LGxxP motif is essential for splicing repressor activity and sufficient for interaction with PTB. An adjacent proline-rich region is also essential for repressor activity but not for PTB interaction. NMR analysis shows that LLGxxP peptides interact with a hydrophobic groove on the dorsal surface of the RRM2 domain of PTB, which constitutes part of the minimal repressor region of PTB. The requirement for the PTB-Raver1 interaction that we have characterized may serve to bring the additional repressor regions of both proteins into a configuration that allows them to synergistically effect exon skipping.

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A peptide motif in Raver1 mediates splicing repression by interaction with the PTB RRM2 domain

Abstract

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