Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Evolution of Interactions Involving Intrinsically Disordered Proteins
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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 [en]
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: urn:nbn:se:uu:diva-336083ISBN: 978-91-513-0226-3 (print)OAI: oai:DiVA.org:uu-336083DiVA, id: diva2:1178141
Public defence
2018-03-16, B41, Biomedicinskt centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilAvailable from: 2018-02-22 Created: 2018-01-28 Last updated: 2018-03-07
List of papers
1. Emergence and evolution of an interaction between intrinsically disordered proteins
Open this publication in new window or tab >>Emergence and evolution of an interaction between intrinsically disordered proteins
Show others...
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.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-322818 (URN)10.7554/eLife.16059 (DOI)000400663100001 ()
Available from: 2017-09-12 Created: 2017-09-12 Last updated: 2018-01-28Bibliographically approved
2. Evolution of the p53-MDM2 pathway
Open this publication in new window or tab >>Evolution of the p53-MDM2 pathway
Show others...
2017 (English)In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 17, article id 177Article in journal (Refereed) Published
Abstract [en]

Background: The p53 signalling pathway, which controls cell fate, has been extensively studied due to its prominent role in tumor development. The pathway includes the tumor supressor protein p53, its vertebrate paralogs p63 and p73, and their negative regulators MDM2 and MDM4. The p53/p63/p73-MDM system is ancient and can be traced in all extant animal phyla. Despite this, correct phylogenetic trees including both vertebrate and invertebrate species of the p53/p63/p73 and MDM families have not been published. Results: Here, we have examined the evolution of the p53/p63/p73 protein family with particular focus on the p53/ p63/p73 transactivation domain (TAD) and its co-evolution with the p53/p63/p73- binding domain (p53/p63/p73BD) of MDM2. We found that the TAD and p53/p63/p73BD share a strong evolutionary connection. If one of the domains of the protein is lost in a phylum, then it seems very likely to be followed by loss of function by the other domain as well, and due to the loss of function it is likely to eventually disappear. By focusing our phylogenetic analysis to p53/p63/ p73 and MDM proteins from phyla that retain the interaction domains TAD and p53/p63/p73BD, we built phylogenetic trees of p53/p63/p73 and MDM based on both vertebrate and invertebrate species. The trees follow species evolution and contain a total number of 183 and 98 species for p53/p63/p73 and MDM, respectively. We also demonstrate that the p53/p63/p73 and MDM families result from whole genome duplications. Conclusions: The signaling pathway of the TAD and p53/p63/p73BD in p53/p63/p73 and MDM, respectively, dates back to early metazoan time and has since then tightly co-evolved, or disappeared in distinct lineages.

Place, publisher, year, edition, pages
BioMed Central, 2017
Keywords
p53, MDM, Co-evolution, Phylogeny
National Category
Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-334047 (URN)10.1186/s12862-017-1023-y (DOI)000407013500001 ()28774266 (PubMedID)
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2018-01-28Bibliographically approved
3. Conservation and divergence in the evolution of binding affinity between p53 and MDM2
Open this publication in new window or tab >>Conservation and divergence in the evolution of binding affinity between p53 and MDM2
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-336917 (URN)
Funder
Swedish Research Council
Available from: 2017-12-18 Created: 2017-12-18 Last updated: 2018-01-28
4. The binding kinetics of the intrinsically disordered p53 family transactivation domains and MDM2
Open this publication in new window or tab >>The binding kinetics of the intrinsically disordered p53 family transactivation domains and MDM2
(English)Manuscript (preprint) (Other academic)
National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-336918 (URN)
Funder
Swedish Research Council
Available from: 2017-12-18 Created: 2017-12-18 Last updated: 2018-01-28

Open Access in DiVA

fulltext(1669 kB)131 downloads
File information
File name FULLTEXT01.pdfFile size 1669 kBChecksum SHA-512
5345b91849a3d25092388f19048e6770e4f58346f12162f06459becab7fa2e4e3f7e216eeac0699b0d97a9b96c963eefef8755db6256bdb35afb24f416d6891f
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Åberg, Emma
By organisation
Department of Medical Biochemistry and Microbiology
Bioinformatics (Computational Biology)Biochemistry and Molecular BiologyBiophysics

Search outside of DiVA

GoogleGoogle Scholar
Total: 131 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 691 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf