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Membrane-protein topology

Nature Reviews Molecular Cell Biology volume 7, pages 909–918 (2006)Cite this article

Key Points

  • The topology of an integral membrane protein describes the number and approximate locations in the sequence of the transmembrane segments, as well as the overall orientation of the protein in a membrane.

  • Topology is controlled primarily by the hydrophobicity and length of transmembrane helices as well as the distribution of positively charged residues in the loops that connect the helices.

  • In most cases, topology is determined co-translationally during the translocon-mediated insertion of a polypeptide into a membrane.

  • Topologies in which both the N terminus and the C terminus of a protein are in the cytoplasm are predominant in both prokaryotic and eukaryotic cells.

  • Membrane proteins evolve primarily by gene duplication and gene fusion. Many membrane proteins form dimers in which the two homologous chains have the same topology (parallel dimer) or opposite topologies (antiparallel dimer). Gene fusions create internally duplicated structures in which the two halves of a protein are orientated either in a parallel or an antiparallel manner.

Abstract

In the world of membrane proteins, topology defines an important halfway house between the amino-acid sequence and the fully folded three-dimensional structure. Although the concept of membrane-protein topology dates back at least 30 years, recent advances in the field of translocon-mediated membrane-protein assembly, proteome-wide studies of membrane-protein topology and an exponentially growing number of high-resolution membrane-protein structures have given us a deeper understanding of how topology is determined and of how it evolves.

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Figure 1: Helix-bundle membrane proteins.
Figure 2: Different amino acids have distinct preferences for different parts of the membrane.
Figure 3: Recognition of a transmembrane helix by the Sec61 translocon.
Figure 4: The distribution of topologies in membrane proteomes.
Figure 5: The candidate dual-topology protein EmrE from Escherichia coli.
Figure 6: Dynamic topologies.
Figure 7: Topology evolution.

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Acknowledgements

Gunnar von Heijne is supported by grants from the Swedish Foundation for Strategic Research, the Marianne and Marcus Wallenberg Foundation, the Swedish Cancer Foundation, the Swedish Research Council and the European Commission (BioSapiens).

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Center for Biomembrane Research and Stockholm Bioinformatics Center, Stockholm University, Stockholm, SE-10691

    Gunnar von Heijne

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Supplementary information

Supplementary information S1 (movie)

S1 (movie) | Bacteriorhodopsin. The structure of bacteriorhodopsin1 (Protein Data Bank accession code 2BRD). The seven transmembrane helices are shown in purple, the light-absorbing retinal is shown in green and positively charged residues are shown in yellow (note the higher number of positively charged residues on the cytoplasmic side, which is at the base of the structure). This movie was made using the Visual Molecular Dynamics software2 (www.ks.uiuc.edu/Research/vmd). (MPG 2371 kb)

References

1. Grigorieff, N., Ceska, T. A., Downing, K. H., Baldwin, J. M. & Henderson, R. Electroncrystallographic refinement of the structure of bacteriorhodopsin. J. Mol. Biol. 259, 393–421 (1996).

2. Humphrey, W., Dalke, A. & Schulten, K. VMD - Visual Molecular Dynamics. J. Mol. Graphics 14, 33–38 (1996).

Supplementary information S2 (movie)

S2 (movie) | Escherichia coli ClC Cl–/H+ antiporter. The structure of the E. coli ClC Cl–/H+ antiporter1 (Protein Data Bank accession code 1KPK). The two subunits in the homodimer are shown in red and blue. Chloride ions are shown in yellow. This movie was made using the Visual Molecular Dynamics software2 (www.ks.uiuc.edu/Research/vmd). (MPG 2870 kb)

References

1. Dutzler, R., Campbell, E. B., Cadene, M., Chait, B. T. & MacKinnon, R. X-ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity. Nature 415, 287–294 (2002).

2. Humphrey, W., Dalke, A. & Schulten, K. VMD - Visual Molecular Dynamics. J. Mol. Graphics 14, 33–38 (1996).

Supplementary information S3 (movie)

S3 (movie) | Bovine Ca2+-ATPase. Conformation changes in Ca2+-ATPase for the transitions E2 → E1·2Ca2+ → E1·ATP → E1P·ADP → E1P → E2P, based on crystal structures of the different intermediate states. The cytoplasmic actuator, nucleotide binding and phosphorylation domains are shown in blue, dark green and light green, respectively. Note the large conformational changes in the transmembrane domain during the reaction cycle. This movie was reproduced with permission from REF. 1. (MOV 1528 kb)

References

1. Toyoshima, C., Nomura, H. & Tsuda, T. Lumenal gating mechanism revealed in calcium pump crystal structures with phosphate analogues. Nature 432, 361–368 (2004).

Supplementary information S4 (movie)

S4 (movie) | The candidate dual-topology protein EmrE from Escherichia coli. The structure of EmrE (REF 1) (Protein Data Bank accession code 2F2M) is shown with the two identical, but oppositely orientated, chains coloured red and blue. The strictly conserved Glu14 residues are shown in green, and the positively charged residues in one of the two chains are shown in yellow. This movie was made using the Visual Molecular Dynamics software2 (www.ks.uiuc.edu/Research/vmd) (MPG 1908 kb)

Reference

1. Pornillos, O., Chen, Y. J., Chen, A. P. & Chang, G. X-ray structure of the EmrE multidrug transporter in complex with a substrate. Science 310, 1950–1953 (2005).

2. Humphrey, W., Dalke, A. & Schulten, K. VMD - Visual Molecular Dynamics. J. Mol. Graphics 14, 33–38 (1996).

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DATABASES

Pfam

DUF606

Protein Data Bank

1KPK

1T5S

2BRD

2F2M

FURTHER INFORMATION

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Center for Biomembrane Research

Membrane Protein Resources

Visual Molecular Dynamics software

Glossary

Topology

A specification of the number of transmembrane helices and their in and/or out orientations across the membrane in a membrane protein.

Fold space

The abstract space of all protein folds.

'Knobs-into-holes' geometry

The classic mode of helix–helix packing in which side-chains on one helix fit into spaces between side chains on the opposite helix.

Retinal

The light-sensitive cofactor in bacteriorhodopsin that absorbs photons and triggers a conformational change in the protein.

Electrochemical gradient

The combined pH and electrostatic gradient across a membrane.

S4 transmembrane helix

A positively charged transmembrane helix that forms part of the voltage-sensor domain in voltage-dependent ion channels.

Helical hairpin

A pair of closely spaced transmembrane helices that is connected by a short extracytoplasmic loop.

V-type ATPase

Ion-pumping ATP synthase located in intracellular organelles.

Connexin channel

A component of gap junctions.

Gap junction

A structure that connects neighbouring cells and allows ions and small molecules to pass between cells.

Scrapie prion protein

An aggregation-prone protein that causes the Scrapie disease in sheep and goats.

Signal peptide

An N-terminal extension on secretory proteins that serves to target a protein to the Sec61 translocon.

Lipid flip–flop

The process whereby a lipid molecule flips between the two leaflets of a lipid bilayer.

Polyprotein

Proteins made as a single polypeptide chain that is cleaved into smaller proteins by cellular proteases.

Domain recombination

An evolutionary process in which pre-existing protein domains are fused in new combinations, creating multidomain, multifunctional polypeptides.

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von Heijne, G. Membrane-protein topology. Nat Rev Mol Cell Biol 7, 909–918 (2006). https://doi.org/10.1038/nrm2063

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