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Emergence and evolution of an interaction between intrinsically disordered proteins
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Univ Cambridge, Dept Chem, Cambridge, England.;Tech Univ Munich, Dept Chem, Munich, Germany.;Tech Univ Munich, Inst Adv Study, Munich, Germany..
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
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2017 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e16059Article in journal (Refereed) Published
Abstract [en]

Protein-protein interactions involving intrinsically disordered proteins are important for cellular function and common in all organisms. However, it is not clear how such interactions emerge and evolve on a molecular level. We performed phylogenetic reconstruction, resurrection and biophysical characterization of two interacting disordered protein domains, CID and NCBD. CID appeared after the divergence of protostomes and deuterostomes 450-600 million years ago, while NCBD was present in the protostome/deuterostome ancestor. The most ancient CID/NCBD formed a relatively weak complex (K(d similar to)5 mu M). At the time of the first vertebrate-specific whole genome duplication, the affinity had increased (K-d\similar to 200 nM) and was maintained in further speciation. Experiments together with molecular modeling using NMR chemical shifts suggest that new interactions involving intrinsically disordered proteins may evolve via a low-affinity complex which is optimized by modulating direct interactions as well as dynamics, while tolerating several potentially disruptive mutations.

Place, publisher, year, edition, pages
2017. Vol. 6, article id e16059
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-322818DOI: 10.7554/eLife.16059ISI: 000400663100001OAI: oai:DiVA.org:uu-322818DiVA, id: diva2:1140505
Available from: 2017-09-12 Created: 2017-09-12 Last updated: 2018-01-28Bibliographically approved
In thesis
1. Evolution of Interactions Involving Intrinsically Disordered Proteins
Open this publication in new window or tab >>Evolution of Interactions Involving Intrinsically Disordered Proteins
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the evolution of intrinsically disordered proteins and their interaction partners. The work presented is a combination of phylogenetic analysis, ancestral reconstruction and biophysical characterization in order to examine the evolutionary trajectory of protein-protein interactions involving disorder. The intrinsically disordered domains, NCBD and CID are both part of transcriptional co-regulating proteins. In evolution, NCBD existed before the emergence of CID and the most ancient domains display a low affinity complex with many weak contacts and high degree of conformational heterogeneity. Later in evolution, when NCBD and CID co-exists, a few mutations have altered the interaction in a way that the affinity is increased 25-fold and the conformational heterogeneity is decreased. In the same manner, the interaction is further optimized in extant species, resulting in a high affinity complex with less contacts of higher strength and less conformational heterogeneity. The intrinsically disordered transactivation domain of the tumour suppressing protein p53 and its negative regulator MDM2 date back to the beginning of animal life. The interacting domains are either lost or conserved in distinct phyla indicating a tight co-evolution. Phylogenetic trees produced by only including phyla with a conserved interaction domain follow the species evolution. Resurrection of p53 and MDM2 in the vertebrate lineage display an evolution of a high affinity complex in the ancestor of fish and tetrapods to a slightly improved affinity in modern tetrapods but a substantially lower affinity in zebrafish. The p53 protein family, which also includes p63 and p73, diverged from a common ancestor. The individual proteins display altered affinities to MDM2 which is a result of the high sequence divergence between them. The ionic dependence for the interactions is small, and not in line with other studies of disordered proteins. In conclusion, the work in this thesis have contributed with evolutionary analysis and experimental data of interactions involving intrinsically disordered proteins.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 44
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1424
Keywords
intrinsically disordered proteins, protein evolution, phylogenetics, ancestral sequence reconstruction, biophysical characterization, NCBD, CID, p53, MDM2
National Category
Bioinformatics (Computational Biology) Biochemistry and Molecular Biology Biophysics
Research subject
Biology with specialization in Molecular Evolution; Biochemistry
Identifiers
urn:nbn:se:uu:diva-336083 (URN)978-91-513-0226-3 (ISBN)
Public defence
2018-03-16, B41, Biomedicinskt centrum, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Funder
Swedish Research Council
Available from: 2018-02-22 Created: 2018-01-28 Last updated: 2018-03-07

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Hultqvist, GretaÅberg, EmmaSundell, GustavAndersson, EvaDogan, JakobJemth, Per

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