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Cell entry machines: a common theme in nature?

Nature Reviews Microbiology volume 3, pages 349–358 (2005)Cite this article

Abstract

Molecular machines orchestrate the translocation and entry of pathogens through host cell membranes, in addition to the uptake and release of molecules during endocytosis and exocytosis. Viral cell entry requires a family of glycoproteins, and the structural organization and function of these viral glycoproteins are similar to the SNARE proteins, which are known to be involved in intracellular vesicle fusion, endocytosis and exocytosis. Here, we propose that a family of bacterial membrane proteins that are responsible for cell-mediated adherence and entry resembles the structural architecture of both viral fusion proteins and eukaryotic SNAREs and might therefore share similar, but distinct, mechanisms of cell membrane translocation. Furthermore, we propose that the recurrence of these molecular machines across species indicates that these architectural motifs were evolutionarily selected because they provided the best solution to ensure the survival of pathogens within a particular environment.

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Figure 1: Schematic representation of intracellular vesicle exocytosis, and viral and bacterial cell entry.
Figure 2: Architecture of eukaryotic membrane and viral fusion proteins compared with bacterial invasins.
Figure 3: Intracellular signalling events.

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Acknowledgements

The authors would like to thank S. Savino, B. Capecchi, J. Adu-Bobie, M. Pizza and B. Aricò for sharing unpublished data on the NadA protein, crucial to support our hypotheses. They are also grateful to M. Scarselli for help in structural model reconstruction of the discussed proteins, and to K. Stadler and I. Ferlenghi for useful discussion and advice. A special acknowledgment goes to G. Corsi for artwork and to C. Mallia for assistance in manuscript preparation.

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Authors and Affiliations

  1. Department of Bioinformatics and Cellular Microbiology, Chiron Vaccines, Via Fiorentina 1, Siena, 53100, Italy

    Michèle A. Barocchi, Vega Masignani & Rino Rappuoli

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  1. Michèle A. Barocchi
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  2. Vega Masignani
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  3. Rino Rappuoli
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Corresponding author

Correspondence to Rino Rappuoli.

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DATABASES

Swiss-Prot

Cdc42

InvA

NadA

UspA1

UspA2

VAMP1

WASP

YadA

FURTHER INFORMATION

PDB protein databank

Glossary

CIRCULAR DICHROISM SPECTRUM ANALYSIS

A widely used technique for obtaining information about protein structure and conformation. It is a sensitive and reliable tool to study the structure and stability of proteins.

COILED COIL

An important protein–protein interaction motif often used to control oligomerization, characterized by a conserved heptad repeat. Coiled coils consist of helices that wrap around one another with a superhelical twist.

FUSION PEPTIDE

A sequence of 20–30 mainly hydrophobic residues (Ala and Gly) found at the N-terminus of the stalk exposed after a conformational change of the viral fusion protein. Insertion of the peptide into the host cell membrane leads to cell fusion events.

HEPTAD REPEAT

Seven residue patterns denoted (abcdefg)n in which the a and d residues (core positions) are generally hydrophobic. As there are 3.6 residues to each turn of the α-helix, these a and d residues form a hydrophobic seam, which, as each heptad is slightly under two turns, slowly twists around a helix. Heptad repeats are characteristic of certain proteins such as the intermediate filament proteins.

INVASIN

Any bacterial surface protein that provokes endocytic uptake by host cells. Adhesins, on the other hand, promote binding to cell surface receptors, but do not elicit uptake by the host cell.

JELLY-ROLL MOTIF

These motifs are found in proteins in which the primary fold contains only β-antiparallel strands. Like other elements of super-secondary structure involving the β-strand (for example, the β–α–α–β unit) the known structure forms a right-handed superhelix.

LINNAEAN APPROACH

The first formal classification scheme was created by Carolus Linnaeus and relied on classification of species according to hierarchical structure, from most general to most similar. However, this scheme ignores their evolutionary history, and important aspects of the origin of those similarities and differences are overlooked.

SNAREs

Soluble NSF (N-ethylmaleimide-sensitive fusion protein) accessory protein (SNAP) receptor). These proteins contain a heptad repeat of 60–90 residues that participate in coiled-coil formation. The family of SNARE proteins are involved in intracellular fusion events.

THREADING ANALYSIS

This method uses computer modelling to obtain structural information based on the amino-acid sequence of an uncharacterized protein structure. Threading analysis is mostly used to detect remote homologues that can not be detected by standard sequence alignment.

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Barocchi, M., Masignani, V. & Rappuoli, R. Cell entry machines: a common theme in nature?. Nat Rev Microbiol 3, 349–358 (2005). https://doi.org/10.1038/nrmicro1131

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