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Unveiling the dimer/monomer propensities of Smad MH1-DNA complexes

View ORCID ProfileLidia Ruiz, View ORCID ProfileZuzanna Kaczmarska, Tiago Gomes, View ORCID ProfileEric Aragón, View ORCID ProfileCarles Torner, View ORCID ProfileRegina Freier, View ORCID ProfileBłażej Bagiński, View ORCID ProfilePau Martin-Malpartida, View ORCID ProfileNatalia de Martin Garrido, José A. Márquez, View ORCID ProfileTiago Cordeiro, View ORCID ProfileRadoslaw Pluta, View ORCID ProfileMaria J. Macias
doi: https://doi.org/10.1101/833319
Lidia Ruiz
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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Zuzanna Kaczmarska
bEMBL Grenoble, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France
cInternational Institute of Molecular and Cell Biology, Trojdena 4, 02-109, Warsaw, Poland
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Tiago Gomes
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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Eric Aragón
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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Carles Torner
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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Regina Freier
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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Błażej Bagiński
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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Pau Martin-Malpartida
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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Natalia de Martin Garrido
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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José A. Márquez
bEMBL Grenoble, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France
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Tiago Cordeiro
dInstituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade NOVA de Lisboa, Av. da República, 2780-157 Oeiras, Portugal
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Radoslaw Pluta
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
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  • For correspondence: radoslaw.pluta@irbbarcelona.org maria.macias@irbbarcelona.org
Maria J. Macias
aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona 08028, Spain
eICREA, Passeig Lluís Companys 23, 08010-Barcelona, Spain
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  • For correspondence: radoslaw.pluta@irbbarcelona.org maria.macias@irbbarcelona.org
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Summary

R-Smads are effectors of the transforming growth factor β (TGFβ) superfamily and along with Smad4 form trimers to interact with DNA. The 5GC-DNA complexes determined here by X-ray crystallography for Smad5 and Smad8 proteins corroborate that all MH1 domains bind SBE and 5GC sites similarly, although Smad2/3/4 MH1 domains bind DNA as monomers whereas Smad1/5/8 form helix-swapped dimers. To examine the relevance of the dimerization phenomenon and to exclude a possible crystallography-induced dimeric state, we studied these MH1 domains in solution. As in the crystals, Smad5/8 domains populate dimers and open monomers in equilibrium, whereas Smad/3/4 ones adopt monomeric closed conformations. We also found that swapping the loop1-sequence between Smad5 and Smad3 results in the chimera-DNA complex crystallizing as a monomer, revealing that the loop1-sequence determines the monomer/dimer propensity of Smad MH1-domains.

We propose that distinct MH1-dimerization status of TGFβ and BMP activated Smads influences the interaction with specific loci genome-wide by distinct R-Smad and Smad4 complexes.

Significance TGFβ- and BMP-activated R-Smads were believed to have different preferences with respect to the recognition of DNA motifs and to respond to specific activation inputs. However, recent results indicate that several types of R-Smads can be activated by similar receptors and that all Smads might recognize various DNA motifs. These results pose new questions as to why different types of R-Smads have been conserved for more than 500 million years if they could have a redundant function. They also raise questions as to how different Smad complexes recognize specific clusters of DNA motifs genome-wide.

Here, using structural biology approaches, we elucidate some of the rules that help define dimers of Smad-DNA complexes and propose how these complexes could influence the recognition of specific cis regulatory elements genome-wide.

Highlights R-Smads and Smad4 interact with GGCGCx and GTCT sites using a conserved binding mode.

Functional differences of TGFβ- and BMP-activated R-Smads are not exclusively related to DNA specificity.

Dimer/monomer propensities are detected in solution and in the absence of DNA.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 07, 2019.
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Unveiling the dimer/monomer propensities of Smad MH1-DNA complexes
Lidia Ruiz, Zuzanna Kaczmarska, Tiago Gomes, Eric Aragón, Carles Torner, Regina Freier, Błażej Bagiński, Pau Martin-Malpartida, Natalia de Martin Garrido, José A. Márquez, Tiago Cordeiro, Radoslaw Pluta, Maria J. Macias
bioRxiv 833319; doi: https://doi.org/10.1101/833319
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Unveiling the dimer/monomer propensities of Smad MH1-DNA complexes
Lidia Ruiz, Zuzanna Kaczmarska, Tiago Gomes, Eric Aragón, Carles Torner, Regina Freier, Błażej Bagiński, Pau Martin-Malpartida, Natalia de Martin Garrido, José A. Márquez, Tiago Cordeiro, Radoslaw Pluta, Maria J. Macias
bioRxiv 833319; doi: https://doi.org/10.1101/833319

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