Conformational landscape of multidomain SMAD proteins
SMAD transcription factors, the main effectors of the TGFβ (transforming growth factor β) network, have a mixed architecture of globular domains and flexible linkers. Such a complicated architecture precluded the description of their full-length (FL) structure for many years. In this study, we unrav...
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doaj-6ffb0740739c4e5897f2e9b46bc8698c2021-09-25T05:06:00ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011952105224Conformational landscape of multidomain SMAD proteinsTiago Gomes0Pau Martin-Malpartida1Lidia Ruiz2Eric Aragón3Tiago N. Cordeiro4Maria J. Macias5Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, SpainInstitute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, SpainInstitute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, SpainInstitute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, SpainInstituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade NOVA de Lisboa, Av. da República, 2780-157 Oeiras, Portugal; Corresponding authors at: Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain (M.J. Macias); Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade NOVA de Lisboa, Av. da República, 2780-157 Oeiras, Portugal (T.N. Cordeiro).Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain; ICREA, Passeig Lluís Companys 23, Barcelona 08010, Spain; Corresponding authors at: Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain (M.J. Macias); Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade NOVA de Lisboa, Av. da República, 2780-157 Oeiras, Portugal (T.N. Cordeiro).SMAD transcription factors, the main effectors of the TGFβ (transforming growth factor β) network, have a mixed architecture of globular domains and flexible linkers. Such a complicated architecture precluded the description of their full-length (FL) structure for many years. In this study, we unravel the structures of SMAD4 and SMAD2 proteins through an integrative approach combining Small-angle X-ray scattering, Nuclear Magnetic Resonance spectroscopy, X-ray, and computational modeling. We show that both proteins populate ensembles of conformations, with the globular domains tethered by disordered and flexible linkers, which defines a new dimension of regulation. The flexibility of the linkers facilitates DNA and protein binding and modulates the protein structure. Yet, SMAD4FL is monomeric, whereas SMAD2FL is in different monomer–dimer-trimer states, driven by interactions of the MH2 domains. Dimers are present regardless of the SMAD2FL activation state and concentration. Finally, we propose that SMAD2FL dimers are key building blocks for the quaternary structures of SMAD complexes.http://www.sciencedirect.com/science/article/pii/S2001037021003949Intrinsically disordered regionsMulti-domain proteinsSMADTranscription factorTGFβ signaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tiago Gomes Pau Martin-Malpartida Lidia Ruiz Eric Aragón Tiago N. Cordeiro Maria J. Macias |
spellingShingle |
Tiago Gomes Pau Martin-Malpartida Lidia Ruiz Eric Aragón Tiago N. Cordeiro Maria J. Macias Conformational landscape of multidomain SMAD proteins Computational and Structural Biotechnology Journal Intrinsically disordered regions Multi-domain proteins SMAD Transcription factor TGFβ signaling |
author_facet |
Tiago Gomes Pau Martin-Malpartida Lidia Ruiz Eric Aragón Tiago N. Cordeiro Maria J. Macias |
author_sort |
Tiago Gomes |
title |
Conformational landscape of multidomain SMAD proteins |
title_short |
Conformational landscape of multidomain SMAD proteins |
title_full |
Conformational landscape of multidomain SMAD proteins |
title_fullStr |
Conformational landscape of multidomain SMAD proteins |
title_full_unstemmed |
Conformational landscape of multidomain SMAD proteins |
title_sort |
conformational landscape of multidomain smad proteins |
publisher |
Elsevier |
series |
Computational and Structural Biotechnology Journal |
issn |
2001-0370 |
publishDate |
2021-01-01 |
description |
SMAD transcription factors, the main effectors of the TGFβ (transforming growth factor β) network, have a mixed architecture of globular domains and flexible linkers. Such a complicated architecture precluded the description of their full-length (FL) structure for many years. In this study, we unravel the structures of SMAD4 and SMAD2 proteins through an integrative approach combining Small-angle X-ray scattering, Nuclear Magnetic Resonance spectroscopy, X-ray, and computational modeling. We show that both proteins populate ensembles of conformations, with the globular domains tethered by disordered and flexible linkers, which defines a new dimension of regulation. The flexibility of the linkers facilitates DNA and protein binding and modulates the protein structure. Yet, SMAD4FL is monomeric, whereas SMAD2FL is in different monomer–dimer-trimer states, driven by interactions of the MH2 domains. Dimers are present regardless of the SMAD2FL activation state and concentration. Finally, we propose that SMAD2FL dimers are key building blocks for the quaternary structures of SMAD complexes. |
topic |
Intrinsically disordered regions Multi-domain proteins SMAD Transcription factor TGFβ signaling |
url |
http://www.sciencedirect.com/science/article/pii/S2001037021003949 |
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1717369154069069824 |