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Identification and evolution of dual-topology membrane proteins
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2006 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 13, no 2, 112-116 p.Article in journal (Refereed) Published
Abstract [en]

Integral membrane proteins are generally believed to have unique membrane topologies. However, it has been suggested that dual-topology proteins that adopt a mixture of two opposite orientations in the membrane may exist. Here we show that the membrane orientations of five dual-topology candidates identified in Escherichia coli are highly sensitive to changes in the distribution of positively charged residues, that genes in families containing dual-topology candidates occur in genomes either as pairs or as singletons and that gene pairs encode two oppositely oriented proteins whereas singletons encode dual-topology candidates. Our results provide strong support for the existence of dual-topology proteins and shed new light on the evolution of membrane-protein topology and structure.

Place, publisher, year, edition, pages
2006. Vol. 13, no 2, 112-116 p.
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-23012DOI: 10.1038/nsmb1057OAI: oai:DiVA.org:su-23012DiVA: diva2:189899
Available from: 2006-10-29 Created: 2006-10-29 Last updated: 2011-09-23Bibliographically approved
In thesis
1. The Ins and Outs of Membrane Proteins: Topology Studies of Bacterial Membrane Proteins
Open this publication in new window or tab >>The Ins and Outs of Membrane Proteins: Topology Studies of Bacterial Membrane Proteins
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

α-helical membrane proteins comprise about a quarter of all proteins in a cell and carry out a wide variety of essential cellular functions. This thesis is focused on topology analyses of bacterial membrane proteins. The topology describes the two-dimensional structural arrangement of a protein relative to the membrane.

By combining large-scale experimental and bioinformatics techniques we have produced experimentally constrained topology models for the major part of the Escherichia coli membrane proteome. This represents a substantial increase in available topology information for bacterial membrane proteins.

Many membrane protein structures show signs of internal duplication and approximate two-fold in-plane symmetry. We propose a step-wise pathway to explain how proteins with such internal inverted repeats have evolved. The pathway is based on the ‘positive-inside’ rule and starts with a protein that can adopt two topologies in the membrane, i.e. a “dual” topology protein. The gene encoding the dual topology protein is duplicated and eventually, through re-distribution of positively charge residues, the two resulting homologous proteins become fixed in opposite orientations in the membrane. Finally, the two proteins may fuse into one single polypeptide with an internal inverted repeat structure.

Finally, we re-create the proposed step-wise evolutionary pathway in the laboratory by showing that only a small number of mutations are required in order to transform the homo-dimeric, dual topology protein EmrE into a hetero-dimeric complex composed of two oppositely oriented proteins.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik, 2006. 58 p.
Keyword
membrane protein, topology, dual topology
National Category
Dentistry
Identifiers
urn:nbn:se:su:diva-1330 (URN)91-7155-311-8 (ISBN)
Public defence
2006-12-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2006-10-29 Created: 2006-10-29 Last updated: 2010-08-25Bibliographically approved
2. Dual-topology membrane proteins in Escherichia coli
Open this publication in new window or tab >>Dual-topology membrane proteins in Escherichia coli
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cellular life, as we know it, is absolutely dependent on biological membranes; remarkable superstructures made of lipids and proteins. For example, all living cells are surrounded by at least one membrane that protects the cell and holds it together. The proteins that are embedded in the membranes carry out a wide variety of key functions, from nutrient uptake and waste disposal to cellular respiration and communication. In order to function accurately, any integral membrane protein needs to be inserted into the cellular membrane where it belongs, and in that particular membrane it has to attain its proper structure and find partners that might be required for proper function. All membrane proteins have evolved to be inserted in a specific overall orientation, so that e.g. substrate-binding parts are exhibited on the ‘right side’ of the membrane. So, what determines in which way a membrane protein is inserted? Are all membrane proteins inserted just so?

The focus of this thesis is on these fundamental questions: how, and when, is the overall orientation of a membrane protein established? A closer look at the inner membrane proteome of the familiar gram-negative bacterium Escherichia coli revealed a small group of proteins that, oddly enough, seemed to be able to insert into the membrane in two opposite orientations. We could show that these dual-topology membrane proteins are delicately balanced, and that even the slightest manipulations make them adopt a fixed orientation in the membrane. Further, we show that these proteins are topologically malleable until the very last residue has been synthesized, implying interesting questions about the topogenesis of membrane proteins in general. In addition, by looking at the distribution of homologous proteins in other organisms, we got some ideas about how membrane proteins might evolve in size and complexity. Structural data has revealed that many membrane bound transporters have internal, inverted symmetries, and we propose that perhaps some of these proteins derive from dual-topology ancestors.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2011. 66 p.
Keyword
membrane protein topology, dual-topology, evolution, Escherichia coli
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-61944 (URN)978-91-7447-351-3 (ISBN)
Public defence
2011-10-28, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2011-10-06 Created: 2011-09-05 Last updated: 2013-04-22Bibliographically approved
3. Structure, prediction, evolution and genome wide studies of membrane proteins
Open this publication in new window or tab >>Structure, prediction, evolution and genome wide studies of membrane proteins
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

α-helical membrane proteins constitute 20-30% of all proteins in a cell and are involved in many essential cellular functions. The structure is only known for a few hundred of them, which makes structural models important. The most common structural model of a membrane protein is the topology which is a two-dimensional representation of the structure.

This thesis is focused on three different aspects of membrane protein structure: improving structural predictions of membrane proteins, improving the level of detail of structural models and the concept of dual topology.

It is possible to improve topology models of membrane proteins by including experimental information in computer predictions. This was first performed in Escherichia coli and, by using homology, it was possible to extend the results to 225 prokaryotic organisms. The improved models covered ~80% of the membrane proteins in E. coli and ~30% of other prokaryotic organisms.

However, the traditional topology concept is sometimes too simple for complex membrane protein structures, which create a need for more detailed structural models. We created two new machine learning methods, one that predicts more structural features of membrane proteins and one that predicts the distance to the membrane centre for the amino acids. These methods improve the level of detail of the structural models.

The final topic of this thesis is dual topology and membrane protein evolution. We have studied a class of membrane proteins that are suggested to insert either way into the membrane, i.e. have a dual topology. These protein families might explain the frequent occurrence of internal symmetry in membrane protein structures.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik, 2007. 47 p.
National Category
Theoretical Chemistry
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-7027 (URN)978-91-7155-489-5 (ISBN)
Public defence
2007-09-24, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2007-08-31 Created: 2007-08-29 Last updated: 2011-09-23Bibliographically approved

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