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The Ins and Outs of Membrane Proteins: Topology Studies of Bacterial Membrane Proteins
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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 [en]
membrane protein, topology, dual topology
National Category
Dentistry
Identifiers
URN: urn:nbn:se:su:diva-1330ISBN: 91-7155-311-8 (print)OAI: oai:DiVA.org:su-1330DiVA: diva2:189901
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
List of papers
1. Experimentally based topology models for E. coli inner membrane proteins
Open this publication in new window or tab >>Experimentally based topology models for E. coli inner membrane proteins
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2004 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 13, no 4, 937-945 p.Article in journal (Refereed) Published
Abstract [en]

Membrane protein topology predictions can be markedly improved by the inclusion of even very limited experimental information. We have recently introduced an approach for the production of reliable topology models based on a combination of experimental determination of the location (cytoplasmic or periplasmic) of a protein's C terminus and topology prediction. Here, we show that determination of the location of a protein's C terminus, rather than some internal loop, is the best strategy for large-scale topology mapping studies. We further report experimentally based topology models for 31 Escherichia coli inner membrane proteins, using methodology suitable for genome-scale studies.

Keyword
membrane proteins, topology, prediction, bioinformatics, fusion protein, PhoA, green fluorescent, protein, FP
Identifiers
urn:nbn:se:su:diva-24327 (URN)10.1110/ps.03553804 (DOI)
Note
Part of urn:nbn:se:su:diva-6875Available from: 2007-05-24 Created: 2007-05-15 Last updated: 2017-12-13Bibliographically approved
2. Global topology analysis of the Escherichia coli inner membrane proteome
Open this publication in new window or tab >>Global topology analysis of the Escherichia coli inner membrane proteome
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2005 In: Science, Vol. 308, no 5726, 1321-1323 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23011 (URN)
Note
Part of urn:nbn:se:su:diva-1330Available from: 2006-10-29 Created: 2006-10-29Bibliographically approved
3. Identification and evolution of dual-topology membrane proteins
Open this publication in new window or tab >>Identification and evolution of dual-topology membrane proteins
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.

National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-23012 (URN)10.1038/nsmb1057 (DOI)
Available from: 2006-10-29 Created: 2006-10-29 Last updated: 2017-12-13Bibliographically approved
4. Emulating membrane protein evolution by rational design
Open this publication in new window or tab >>Emulating membrane protein evolution by rational design
2007 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 315, no 5816, 1282-1284 p.Article in journal (Refereed) Published
Abstract [en]

How do integral membrane proteins evolve in size and complexity? Using the small multidrug-resistance protein EmrE from Escherichia coli as a model, we experimentally demonstrated that the evolution of membrane proteins composed of two homologous but oppositely oriented domains can occur in a small number of steps: An original dual-topology protein evolves, through a gene-duplication event, to a heterodimer formed by two oppositely oriented monomers. This simple evolutionary pathway can explain the frequent occurrence of membrane proteins with an internal pseudo–two-fold symmetry axis in the plane of the membrane.

National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-23013 (URN)10.1126/science.1135406 (DOI)000244564700051 ()
Available from: 2006-10-29 Created: 2006-10-29 Last updated: 2017-12-13Bibliographically approved

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