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Conformational buffering underlies functional selection in intrinsically disordered protein regions

View ORCID ProfileNicolas S. Gonzalez-Foutel, View ORCID ProfileWade M. Borcherds, View ORCID ProfileJuliana Glavina, View ORCID ProfileSusana Barrera-Vilarmau, View ORCID ProfileAmin Sagar, View ORCID ProfileAlejandro Estaña, View ORCID ProfileAmelie Barozet, View ORCID ProfileGregorio Fernandez-Ballester, View ORCID ProfileClara Blanes-Mira, View ORCID ProfileIgnacio E Sánchez, View ORCID ProfileGonzalo de Prat-Gay, View ORCID ProfileJuan Cortés, View ORCID ProfilePau Bernadó, View ORCID ProfileRohit V. Pappu, View ORCID ProfileAlex S. Holehouse, View ORCID ProfileGary W. Daughdrill, View ORCID ProfileLucía B. Chemes
doi: https://doi.org/10.1101/2021.05.14.444182
Nicolas S. Gonzalez-Foutel
1Instituto de Investigaciones Biotecnológicas (IIBiO-CONICET), Universidad Nacional de San Martín, Av. 25 de Mayo y Francia, CP1650 Buenos Aires, Argentina
2Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas (IIB-CONICET), Av. Patricias Argentinas 435, CP1405 Ciudad Autónoma de Buenos Aires, Argentina
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  • ORCID record for Nicolas S. Gonzalez-Foutel
Wade M. Borcherds
3Department of Cell Biology, Microbiology, and Molecular Biology and, University of South Florida. Tampa, Florida
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  • ORCID record for Wade M. Borcherds
Juliana Glavina
1Instituto de Investigaciones Biotecnológicas (IIBiO-CONICET), Universidad Nacional de San Martín, Av. 25 de Mayo y Francia, CP1650 Buenos Aires, Argentina
4Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Universidad de Buenos Aires, Ciudad Universitaria CP1428 Buenos Aires Argentina
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Susana Barrera-Vilarmau
5Department of Biomedical Engineering, Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, USA
6Instituto de Química Avanzada de Cataluña (IQAC-CSIC), Jordi Girona, 18-26, 08034, Barcelona, Spain
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Amin Sagar
7Centre de Biochimie Structurale, INSERM, CNRS, Université de Montpellier, 34090 Montpellier, France
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Alejandro Estaña
7Centre de Biochimie Structurale, INSERM, CNRS, Université de Montpellier, 34090 Montpellier, France
8LAAS-CNRS, Université de Toulouse, CNRS, 31400 Toulouse, France
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Amelie Barozet
8LAAS-CNRS, Université de Toulouse, CNRS, 31400 Toulouse, France
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Gregorio Fernandez-Ballester
9Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, 03202, Alicante, Spain
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Clara Blanes-Mira
9Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, 03202, Alicante, Spain
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Ignacio E Sánchez
4Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Universidad de Buenos Aires, Ciudad Universitaria CP1428 Buenos Aires Argentina
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Gonzalo de Prat-Gay
2Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas (IIB-CONICET), Av. Patricias Argentinas 435, CP1405 Ciudad Autónoma de Buenos Aires, Argentina
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Juan Cortés
8LAAS-CNRS, Université de Toulouse, CNRS, 31400 Toulouse, France
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Pau Bernadó
7Centre de Biochimie Structurale, INSERM, CNRS, Université de Montpellier, 34090 Montpellier, France
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Rohit V. Pappu
5Department of Biomedical Engineering, Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, USA
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  • For correspondence: lchemes@iib.unsam.edu.ar pappu@wustl.edu alex.holehouse@wustl.edu gdaughdrill@usf.edu
Alex S. Holehouse
5Department of Biomedical Engineering, Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, USA
10Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110
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  • For correspondence: lchemes@iib.unsam.edu.ar pappu@wustl.edu alex.holehouse@wustl.edu gdaughdrill@usf.edu
Gary W. Daughdrill
3Department of Cell Biology, Microbiology, and Molecular Biology and, University of South Florida. Tampa, Florida
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  • For correspondence: lchemes@iib.unsam.edu.ar pappu@wustl.edu alex.holehouse@wustl.edu gdaughdrill@usf.edu
Lucía B. Chemes
1Instituto de Investigaciones Biotecnológicas (IIBiO-CONICET), Universidad Nacional de San Martín, Av. 25 de Mayo y Francia, CP1650 Buenos Aires, Argentina
2Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas (IIB-CONICET), Av. Patricias Argentinas 435, CP1405 Ciudad Autónoma de Buenos Aires, Argentina
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  • For correspondence: lchemes@iib.unsam.edu.ar pappu@wustl.edu alex.holehouse@wustl.edu gdaughdrill@usf.edu
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ABSTRACT

Many disordered proteins conserve essential functions in the face of extensive sequence variation. This makes it challenging to identify the forces responsible for functional selection. Viruses are robust model systems to investigate functional selection and they take advantage of protein disorder to acquire novel traits. Here, we combine structural and computational biophysics with evolutionary analysis to determine the molecular basis for functional selection in the intrinsically disordered adenovirus early gene 1A (E1A) protein. E1A competes with host factors to bind the retinoblastoma (Rb) protein, triggering early S-phase entry and disrupting normal cellular proliferation. We show that the ability to outcompete host factors depends on the picomolar binding affinity of E1A for Rb, which is driven by two binding motifs tethered by a hypervariable disordered linker. Binding affinity is determined by the spatial dimensions of the linker, which constrain the relative position of the two binding motifs. Despite substantial sequence variation across evolution, the linker dimensions are finely optimized through compensatory changes in amino acid sequence and sequence length, leading to conserved linker dimensions and maximal affinity. We refer to the mechanism that conserves spatial dimensions despite large-scale variations in sequence as conformational buffering. Conformational buffering explains how variable disordered proteins encode functions and could be a general mechanism for functional selection within disordered protein regions.

Competing Interest Statement

The authors have declared no competing interest.

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Conformational buffering underlies functional selection in intrinsically disordered protein regions
Nicolas S. Gonzalez-Foutel, Wade M. Borcherds, Juliana Glavina, Susana Barrera-Vilarmau, Amin Sagar, Alejandro Estaña, Amelie Barozet, Gregorio Fernandez-Ballester, Clara Blanes-Mira, Ignacio E Sánchez, Gonzalo de Prat-Gay, Juan Cortés, Pau Bernadó, Rohit V. Pappu, Alex S. Holehouse, Gary W. Daughdrill, Lucía B. Chemes
bioRxiv 2021.05.14.444182; doi: https://doi.org/10.1101/2021.05.14.444182
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Conformational buffering underlies functional selection in intrinsically disordered protein regions
Nicolas S. Gonzalez-Foutel, Wade M. Borcherds, Juliana Glavina, Susana Barrera-Vilarmau, Amin Sagar, Alejandro Estaña, Amelie Barozet, Gregorio Fernandez-Ballester, Clara Blanes-Mira, Ignacio E Sánchez, Gonzalo de Prat-Gay, Juan Cortés, Pau Bernadó, Rohit V. Pappu, Alex S. Holehouse, Gary W. Daughdrill, Lucía B. Chemes
bioRxiv 2021.05.14.444182; doi: https://doi.org/10.1101/2021.05.14.444182

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