Conformational landscape of multidomain SMAD proteins

被引:15
作者
Gomes, Tiago [1 ]
Martin-Malpartida, Pau [1 ]
Ruiz, Lidia [1 ]
Aragon, Eric [1 ]
Cordeiro, Tiago N. [2 ]
Macias, Maria J. [1 ,3 ]
机构
[1] Barcelona Inst Sci & Technol, Inst Res Biomed, Baldiri Reixac 10, Barcelona 08028, Spain
[2] Univ NOVA Lisboa, Inst Tecnol Quim & Biol Antonio Xavier ITQB, Av Republ, P-2780157 Oeiras, Portugal
[3] ICREA, Passeig Lluis Co 23, Barcelona 08010, Spain
基金
欧盟地平线“2020”;
关键词
Intrinsically disordered regions; Multi-domain proteins; SMAD; Transcription factor; TGF beta signaling; INTRINSICALLY DISORDERED PROTEINS; SMALL-ANGLE SCATTERING; TGF-BETA RECEPTOR; BIOLOGICAL MACROMOLECULES; STRUCTURAL BASIS; SECONDARY STRUCTURE; NMR-SPECTROSCOPY; CELL-MEMBRANE; DYNAMICS; DOMAINS;
D O I
10.1016/j.csbj.2021.09.009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
SMAD transcription factors, the main effectors of the TGFO (transforming growth factor O) 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. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
引用
收藏
页码:5210 / 5224
页数:15
相关论文
共 87 条
[1]   Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers [J].
Abraham, Mark James ;
Murtola, Teemu ;
Schulz, Roland ;
Páll, Szilárd ;
Smith, Jeremy C. ;
Hess, Berk ;
Lindah, Erik .
SoftwareX, 2015, 1-2 :19-25
[2]   Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling [J].
Aragon, Eric ;
Wang, Qiong ;
Zou, Yilong ;
Morgani, Sophie M. ;
Ruiz, Lidia ;
Kaczmarska, Zuzanna ;
Su, Jie ;
Torner, Carles ;
Tian, Lin ;
Hu, Jing ;
Shu, Weiping ;
Agrawal, Saloni ;
Gomes, Tiago ;
Marquez, Jose A. ;
Hadjantonakis, Anna-Katerina ;
Macias, Maria J. ;
Massague, Joan .
GENES & DEVELOPMENT, 2019, 33 (21-22) :1506-1524
[3]   Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-β Pathways [J].
Aragon, Eric ;
Goerner, Nina ;
Xi, Qiaoran ;
Gomes, Tiago ;
Gao, Sheng ;
Massague, Joan ;
Macias, Maria J. .
STRUCTURE, 2012, 20 (10) :1726-1736
[4]   A Smad action turnover switch operated by WW domain readers of a phosphoserine code [J].
Aragon, Eric ;
Goerner, Nina ;
Zaromytidou, Alexia-Ileana ;
Xi, Qiaoran ;
Escobedo, Albert ;
Massague, Joan ;
Macias, Maria J. .
GENES & DEVELOPMENT, 2011, 25 (12) :1275-1288
[5]   The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease [J].
Babu, M. Madan .
BIOCHEMICAL SOCIETY TRANSACTIONS, 2016, 44 :1185-1200
[6]   BACKBONE DYNAMICS OF CALMODULIN STUDIED BY N-15 RELAXATION USING INVERSE DETECTED 2-DIMENSIONAL NMR-SPECTROSCOPY - THE CENTRAL HELIX IS FLEXIBLE [J].
BARBATO, G ;
IKURA, M ;
KAY, LE ;
PASTOR, RW ;
BAX, A .
BIOCHEMISTRY, 1992, 31 (23) :5269-5278
[7]   Structural characterization of flexible proteins using small-angle X-ray scattering [J].
Bernado, Pau ;
Mylonas, Efstratios ;
Petoukhov, Maxim V. ;
Blackledge, Martin ;
Svergun, Dmitri I. .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2007, 129 (17) :5656-5664
[8]   Dynamics and adaptive benefits of modular protein evolution [J].
Bornberg-Bauer, Erich ;
Mar Alba, M. .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 2013, 23 (03) :459-466
[9]   A novel NMR experiment for the sequential assignment of proline residues and proline stretches in 13C/15N-labeled proteins [J].
Bottomley, MJ ;
Macias, MJ ;
Liu, Z ;
Sattler, M .
JOURNAL OF BIOMOLECULAR NMR, 1999, 13 (04) :381-385
[10]   Evolving SAXS versatility: solution X-ray scattering for macromolecular architecture, functional landscapes, and integrative structural biology [J].
Brosey, Chris A. ;
Tainer, John A. .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 2019, 58 :197-213