Conformational landscape of multidomain SMAD proteins.
Intrinsically disordered regions
Multi-domain proteins
SMAD
TGFβ signaling
Transcription factor
Journal
Computational and structural biotechnology journal
ISSN: 2001-0370
Titre abrégé: Comput Struct Biotechnol J
Pays: Netherlands
ID NLM: 101585369
Informations de publication
Date de publication:
2021
2021
Historique:
received:
25
06
2021
revised:
08
09
2021
accepted:
09
09
2021
entrez:
11
10
2021
pubmed:
12
10
2021
medline:
12
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34630939
doi: 10.1016/j.csbj.2021.09.009
pii: S2001-0370(21)00394-9
pmc: PMC8479633
doi:
Types de publication
Journal Article
Langues
eng
Pagination
5210-5224Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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