6m64 | pdb_00006m64

Crystal structure of SMAD2 in complex with CBP

Structural highlights

6m64 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.45Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SMAD2_HUMAN Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Transforming growth factor-beta (TGF-beta) proteins regulate multiple cellular functions, including cell proliferation, apoptosis, and extracellular matrix formation. The dysregulation of TGF-beta signaling causes diseases such as cancer and fibrosis, and therefore, understanding the biochemical basis of TGF-beta signal transduction is important for elucidating pathogenic mechanisms in these diseases. SMAD proteins are transcription factors that mediate TGF-beta signaling-dependent gene expression. The transcriptional coactivator CBP directly interacts with the MH2 domains of SMAD2 to activate SMAD complex-dependent gene expression. Here, we report the structural basis for CBP recognition by SMAD2. The crystal structures of the SMAD2 MH2 domain in complex with the SMAD2-binding region of CBP showed that CBP forms an amphiphilic helix on the hydrophobic surface of SMAD2. The expression of a mutated CBP peptide that showed increased SMAD2 binding repressed SMAD2-dependent gene expression in response to TGF-beta signaling in cultured cells. Disrupting the interaction between SMAD2 and CBP may therefore be a promising strategy for suppressing SMAD-dependent gene expression.

Structural basis for transcriptional coactivator recognition by SMAD2 in TGF-beta signaling.,Miyazono KI, Ito T, Fukatsu Y, Wada H, Kurisaki A, Tanokura M Sci Signal. 2020 Dec 15;13(662):eabb9043. doi: 10.1126/scisignal.abb9043. PMID:33323411^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lebrun JJ, Takabe K, Chen Y, Vale W. Roles of pathway-specific and inhibitory Smads in activin receptor signaling. Mol Endocrinol. 1999 Jan;13(1):15-23. PMID:9892009
↑ Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC, Shi Y, Chen YG, Meng A, Feng XH. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell. 2006 Jun 2;125(5):915-28. PMID:16751101 doi:10.1016/j.cell.2006.03.044
↑ Seong HA, Jung H, Kim KT, Ha H. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins. J Biol Chem. 2007 Apr 20;282(16):12272-89. Epub 2007 Feb 27. PMID:17327236 doi:10.1074/jbc.M609279200
↑ Inoue Y, Itoh Y, Abe K, Okamoto T, Daitoku H, Fukamizu A, Onozaki K, Hayashi H. Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Oncogene. 2007 Jan 25;26(4):500-8. Epub 2006 Jul 24. PMID:16862174 doi:10.1038/sj.onc.1209826
↑ Dai F, Lin X, Chang C, Feng XH. Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling. Dev Cell. 2009 Mar;16(3):345-57. doi: 10.1016/j.devcel.2009.01.022. PMID:19289081 doi:10.1016/j.devcel.2009.01.022
↑ Miyazono KI, Ito T, Fukatsu Y, Wada H, Kurisaki A, Tanokura M. Structural basis for transcriptional coactivator recognition by SMAD2 in TGF-β signaling. Sci Signal. 2020 Dec 15;13(662):eabb9043. PMID:33323411 doi:10.1126/scisignal.abb9043

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OCA

[1] Lebrun JJ, Takabe K, Chen Y, Vale W. Roles of pathway-specific and inhibitory Smads in activin receptor signaling. Mol Endocrinol. 1999 Jan;13(1):15-23. PMID:9892009

[2] Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC, Shi Y, Chen YG, Meng A, Feng XH. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell. 2006 Jun 2;125(5):915-28. PMID:16751101 doi:10.1016/j.cell.2006.03.044

[3] Seong HA, Jung H, Kim KT, Ha H. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins. J Biol Chem. 2007 Apr 20;282(16):12272-89. Epub 2007 Feb 27. PMID:17327236 doi:10.1074/jbc.M609279200

[4] Inoue Y, Itoh Y, Abe K, Okamoto T, Daitoku H, Fukamizu A, Onozaki K, Hayashi H. Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Oncogene. 2007 Jan 25;26(4):500-8. Epub 2006 Jul 24. PMID:16862174 doi:10.1038/sj.onc.1209826

[5] Dai F, Lin X, Chang C, Feng XH. Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling. Dev Cell. 2009 Mar;16(3):345-57. doi: 10.1016/j.devcel.2009.01.022. PMID:19289081 doi:10.1016/j.devcel.2009.01.022

[6] Miyazono KI, Ito T, Fukatsu Y, Wada H, Kurisaki A, Tanokura M. Structural basis for transcriptional coactivator recognition by SMAD2 in TGF-β signaling. Sci Signal. 2020 Dec 15;13(662):eabb9043. PMID:33323411 doi:10.1126/scisignal.abb9043

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6m64 | pdb_00006m64

Crystal structure of SMAD2 in complex with CBP

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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