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  • Final Report Summary - TAT MACHINE (Functional genomic characterization of the bacterial Tat complex as a nanomachine for biopharmaceutical production and a target for novel anti-infectives)
FP6

TAT MACHINE Informe resumido

Project ID: 5257
Financiado con arreglo a: FP6-LIFESCIHEALTH
País: Netherlands

Final Report Summary - TAT MACHINE (Functional genomic characterization of the bacterial Tat complex as a nanomachine for biopharmaceutical production and a target for novel anti-infectives)

Bacteria export numerous proteins across the plasma membrane into the periplasmic space / outer membrane (Gram-negative organisms), or the medium (Gram-positive organisms). In most bacteria, the bulk of this export traffic is mediated by the general secretory (Sec) pathway, which culminates in the threading of the substrate protein through a membrane-bound Sec translocon in a largely unfolded state. The exported protein then folds on the trans-side of the membrane. More recently, a second mainstream export was identified: the twin-arginine translocation pathway, which derives its name from the twin-arginine motif that forms a critical determinant in the signal peptide of its substrates. In contrast to the Sec system, the Tat system translocates globular proteins in a folded form. It is unique in terms of both structure and mechanism.

The TAT MACHINE project was focused on the twin-arginine translocation (Tat) protein transporter that is widespread in bacterial plasma membranes. This system assembles to form a circa 1 mDa nanomachine that is uniquely able to translocate a wide range of large, folded (even oligomeric) proteins across the tightly sealed bacterial plasma membrane. The system differs in both structural and mechanistic respects from all other known protein translocases. Although only identified in bacteria in 1998, it is already clear that the system has significant potential for biomedical and biotechnological research and exploitation.

The first and principal objective in the project was to generate a platform for the secretion of a wide range of heterologous proteins, in particular those of therapeutic value, based on the Tat machinery.

The second objective was to obtain a clear picture of the 'global' role of Tat in a range of pathogenic and non-pathogenic organisms, and to obtain detailed information on Tat structure that will lay the foundations for the future design of specific inhibitors. It is already clear that the Tat system is vital for the pathogenesis of a range of bacteria. Some bacteria export major virulence factors by this pathway, and disruption of the Tat pathway otherwise impairs the viability of others. Because the Tat subunits are also unique in structural terms, and completely absent from mammals, the Tat machine represents a superb target for novel anti-infectives.

Efficient Tat-specific signal peptides from Streptomyces are essential for the development of this bacterium as an efficient Tat-dependent secretion system. In particular, since this bacterium is already a natural producer of many antibiotics, this is a very attractive host for the production of secreted bio-pharmaceutical proteins. A considerable number of efficient Tat-specific signal peptides from Streptomyces coelicolor have been identified. It is also clear that very large proteins can be secreted Tat-dependently by this bacterium. Based on these findings, one of the partners has filed an application for a patent.

A public website for the project is available at: http://www.tatmachine.net/. In addition, a public website for the Bacell / BACIP research community is available at: http://www.bacell.eu.

The project has impacted on human health by providing new leads for the exploitation of the Tat pathway for the production of valuable proteins, including bio-pharmaceutical proteins. In addition, Tat components and Tat substrates involved in virulence are potential targets for novel anti-infectives. One patent application (on the exploitation of the Tat pathway in Streptomyces) has already emerged from this work, and another patent application is likely to be filed after the end of the contract.

Información relacionada

Contacto

Jan Maarten VAN DIJL, (Head of Department; coordinator project)
Tel.: +31-50-3633079
Fax: +31-50-3633528
Correo electrónico
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