Extreme disorder in an ultrahigh-affinity protein complex

Alessandro Borgia; Madeleine B. Borgia; Katrine Østergaard Bugge; Vera M. Kissling; Pétur O. Heidarsson; Catarina B. Fernandes; Andrea Sottini; Andrea Soranno; Karin J. Buholzer; Daniel Nettels; Birthe Brandt Kragelund; Robert B. Best; Benjamin Schuler

doi:10.1038/nature25762

Extreme disorder in an ultrahigh-affinity protein complex

Alessandro Borgia, Madeleine B. Borgia, Katrine Østergaard Bugge, Vera M. Kissling, Pétur O. Heidarsson, Catarina B. Fernandes, Andrea Sottini, Andrea Soranno, Karin J. Buholzer, Daniel Nettels, Birthe Brandt Kragelund, Robert B. Best, Benjamin Schuler

235 Citationer (Scopus)

Abstract

Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	555
Sider (fra-til)	61-66
Antal sider	6
ISSN	0028-0836
DOI	https://doi.org/10.1038/nature25762
Status	Udgivet - 1 mar. 2018

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10.1038/nature25762

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title = "Extreme disorder in an ultrahigh-affinity protein complex",

abstract = "Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes.",

author = "Alessandro Borgia and Borgia, {Madeleine B.} and Bugge, {Katrine {\O}stergaard} and Kissling, {Vera M.} and Heidarsson, {P{\'e}tur O.} and Fernandes, {Catarina B.} and Andrea Sottini and Andrea Soranno and Buholzer, {Karin J.} and Daniel Nettels and Kragelund, {Birthe Brandt} and Best, {Robert B.} and Benjamin Schuler",

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AU - Borgia, Alessandro

AU - Borgia, Madeleine B.

AU - Bugge, Katrine Østergaard

AU - Kissling, Vera M.

AU - Heidarsson, Pétur O.

AU - Fernandes, Catarina B.

AU - Sottini, Andrea

AU - Soranno, Andrea

AU - Buholzer, Karin J.

AU - Nettels, Daniel

AU - Kragelund, Birthe Brandt

AU - Best, Robert B.

AU - Schuler, Benjamin

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes.

AB - Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes.

U2 - 10.1038/nature25762

DO - 10.1038/nature25762

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SN - 0028-0836

VL - 555

SP - 61

EP - 66

JO - Nature

JF - Nature

ER -

Extreme disorder in an ultrahigh-affinity protein complex

Abstract

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