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Domain rearrangement and creation in protein evolution
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are composed of domains, recurrent protein fragments with distinct structure, function and evolutionary history. Some domains exist only as single domain proteins, however, a majority of them are also combined with other domains. Domain rearrangements are important in the evolution of new proteins as new functionalities can arise in a single evolutionary event. In addition, the domain repertoire can be expanded through mutations of existing domains and de novo creation. The processes of domain rearrangement and creation have been the focus of this thesis.

According to our estimates about 65% of the eukaryotic and 40% of the prokaryotic proteins are of multidomain type. We found that insertion of a single domain at the N- or C-terminus was the most common event in the creation of novel multidomain architectures. However, domain repeats deviate from this pattern and are often expanded through duplications of several domains. Next, by mapping domain combinations onto an evolutionary tree we estimated that roughly one domain architecture has been created per million years, with the highest rates in metazoa. Much of this so called explosion of new architectures in metazoa seems to be explained by a set of domains amenable to exon shuffling. In contrast to domain architectures, most known domain families evolved early. However, many proteins have incomplete domain coverage, and could hence contain de novo created domains. In Saccharomyces cerevisiae, however, species specific sequences constitute only a minor fraction of the proteome, and are often short, disordered sequences located at the protein termini.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2008. , 50 p.
National Category
Bioinformatics (Computational Biology)
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-8295ISBN: 978-91-7155-767-4 (print)OAI: oai:DiVA.org:su-8295DiVA: diva2:200004
Public defence
2008-11-28, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2008-11-06 Created: 2008-10-27Bibliographically approved
List of papers
1. Multi-domain Proteins in the Three Kingdoms of Life: Orphan Domains and Other Unassigned Regions
Open this publication in new window or tab >>Multi-domain Proteins in the Three Kingdoms of Life: Orphan Domains and Other Unassigned Regions
2005 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 348, no 1, 241-243 p.Article in journal (Refereed) Published
Abstract [en]

Comparative studies of the proteomes from different organisms have provided valuable information about protein domain distribution in the kingdoms of life. Earlier studies have been limited by the fact that only about 50% of the proteomes could be matched to a domain. Here, we have extended these studies by including less well-defined domain definitions, Pfam-B and clustered domains, MAS, in addition to Pfam-A and SCOP domains. It was found that a significant fraction of these domain families are homologous to Pfam-A or SCOP domains. Further, we show that all regions that do not match a Pfam-A or SCOP domain contain a significantly higher fraction of disordered structure. These unstructured regions may be contained within orphan domains or function as linkers between structured domains. Using several different definitions we have re-estimated the number of multi-domain proteins in different organisms and found that several methods all predict that eukaryotes have approximately 65% multi-domain proteins, while the prokaryotes consist of approximately 40% multi-domain proteins. However, these numbers are strongly dependent on the exact choice of cut-off for domains in unassigned regions. In conclusion, all eukaryotes have similar fractions of multidomain proteins and disorder, whereas a high fraction of repeating domain is distinguished only in multicellular eukaryotes. This implies a role for repeats in cell-cell contacts while the other two features are important for intracellular functions.

Keyword
protein domains; multi-domain protein; comparative genomics; kingdoms of life; proteome
Identifiers
urn:nbn:se:su:diva-25575 (URN)10.1016/j.jmb.2005.02.007 (DOI)
Note
Part of urn:nbn:se:su:diva-8295Available from: 2008-11-06 Created: 2008-10-27 Last updated: 2017-12-13Bibliographically approved
2. Domain Rearrangements in Protein Evolution
Open this publication in new window or tab >>Domain Rearrangements in Protein Evolution
Show others...
2005 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 353, no 4, 911-923 p.Article in journal (Refereed) Published
Abstract [en]

Most eukaryotic proteins are multi-domain proteins that are created from fusions of genes, deletions and internal repetitions. An investigation of such evolutionary events requires a method to find the domain architecture from which each protein originates. Therefore, we defined a novel measure, domain distance, which is calculated as the number of domains that differ between two domain architectures. Using this measure the evolutionary events that distinguish a protein from its closest ancestor have been studied and it was found that indels are more common than internal repetition and that the exchange of a domain is rare. Indels and repetitions are common at both the N and C-terminals while they are rare between domains. The evolution of the majority of multi-domain proteins can be explained by the stepwise insertions of single domains, with the exception of repeats that sometimes are duplicated several domains in tandem. We show that domain distances agree with sequence similarity and semantic similarity based on gene ontology annotations. In addition, we demonstrate the use of the domain distance measure to build evolutionary trees. Finally, the evolution of multi-domain proteins is exemplified by a closer study of the evolution of two protein families, non-receptor tyrosine kinases and RhoGEFs.

Keyword
protein evolution; multi-domain proteins; proteome; GOGraph; Pfam
Identifiers
urn:nbn:se:su:diva-25576 (URN)10.1016/j.jmb.2005.08.067 (DOI)
Note
Part of urn:nbn:se:su:diva-8295Available from: 2008-11-06 Created: 2008-10-27 Last updated: 2017-12-13Bibliographically approved
3. Expansion of Protein Domain Repeats
Open this publication in new window or tab >>Expansion of Protein Domain Repeats
2006 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 2, no 8, 959-970 p.Article in journal (Refereed) Published
Abstract [en]

Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e. g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:su:diva-25577 (URN)10.1371/journal.pcbi.0020114 (DOI)
Note

Part of urn:nbn:se:su:diva-8295

Available from: 2008-11-06 Created: 2008-10-27 Last updated: 2017-12-13Bibliographically approved
4. Quantification of the Elevated Rate of Domain Rearrangements in Metazoa
Open this publication in new window or tab >>Quantification of the Elevated Rate of Domain Rearrangements in Metazoa
2007 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 372, no 5, 1337-1348 p.Article in journal (Refereed) Published
Abstract [en]

Most eukaryotic proteins consist of multiple domains created through gene fusions or internal duplications. The most frequent change of a domain architecture (DA) is insertion or deletion of a domain at the N or C terminus. Still, the mechanisms underlying the evolution of multidomain proteins are not very well studied.

Here, we have studied the evolution of multidomain architectures (MDA), guided by evolutionary information in the form of a phylogenetic tree. Our results show that Pfam domain families and MDAs have been created with comparable rates (0.1–1 per million years (My)). The major changes in DA evolution have occurred in the process of multicellularization and within the metazoan lineage. In contrast, creation of domains seems to have been frequent already in the early evolution. Furthermore, most of the architectures have been created from older domains or architectures, whereas novel domains are mainly found in single-domain proteins. However, a particular group of exon-bordering domains may have contributed to the rapid evolution of novel multidomain proteins in metazoan organisms. Finally, MDAs have evolved predominantly through insertions of domains, whereas domain deletions are less common.

In conclusion, the rate of creation of multidomain proteins has accelerated in the metazoan lineage, which may partly be explained by the frequent insertion of exon-bordering domains into new architectures. However, our results indicate that other factors have contributed as well.

Keyword
protein evolution, multidomain protein, Pfam, exon shuffling metazoan evolution
Identifiers
urn:nbn:se:su:diva-25578 (URN)10.1016/j.jmb.2007.06.022 (DOI)000249817500016 ()
Note
Part of urn:nbn:se:su:diva-8295Available from: 2008-11-06 Created: 2008-10-27 Last updated: 2017-12-13Bibliographically approved
5. A study of the origin of orphans in the fungi lineage
Open this publication in new window or tab >>A study of the origin of orphans in the fungi lineage
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25579 (URN)
Note
Part of urn:nbn:se:su:diva-8295Available from: 2008-11-06 Created: 2008-10-27 Last updated: 2010-01-13Bibliographically approved

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