CE09 - Nanomatériaux et nanotechnologies pour les produits du futur

SPATIAL CONTROL WITH HEXAMERIC PROTEIN PLATFORMS – SPACEHex

Submission summary

Synthetic biology continuously demands the development of novel biotechnology tools for the optimization of engineered metabolic cascades. This, in part, can be tackled by optimizing the three-dimensional relative emplacement of designed enzymes. SPACEHex seeks to develop novel protein-based platforms for such purposes. They will be based on the highly modular and assembly-prone hexamer bricks that compose the shells of bacterial micro-compartments (BMC). Taking into account that BMC are structures that host varied types of metabolic processes in vivo, and are therefore naturally adapted for synthetic biology purposes, the novel platforms should be optimal bricks for the conception of future nano-reactors for the encapsulation of engineered metabolic routes.

To reach its main goal, SPACEHex intends to master the relative emplacement within those hexamers of each individual monomer, the attachment points for future engineered domains. After setting up appropriate high-throughput screening methods, optimized to maximize readings of monomer-monomer associations within hexamers, we will first evaluate monomer-monomer interface compatibilities by confronting all possible pairs of homologous isoforms in libraries of sequences selected from genomic databases. Gathered information will be important for the design of hexameric platforms, but is also expected to contribute to our understanding of BMC function. Thus, compatibilities between isoforms of given bacteria could permit to anticipate mechanisms of regulation preventing the formation of hybrid BMC in organisms capable of producing several compartment types.

Experimental data will be exploited to guide the computer-aided design of monomer-monomer interfaces. Rapid and efficient artificial intelligence algorithms for automated reasoning (“cost function networks”) combined with molecular modeling approaches that have been developed by members of this consortium, will be exploited to model and estimate binding affinities for huge numbers of pairs of sequences. Comparison to experimental data is expected to permit the amelioration of theoretical parameters, thus leading to more reliable predictions when studying sequences present in genomic databases. Such feedbacks should permit in fine to define residue determinants for association at monomer-monomer interfaces, guiding decisions for the reconstitution of orthogonal interfaces based on natural sequences. The same computational methods will be also extended to allow multistate decisions, thus allowing the automatic rejection of monomer sequences that would cause promiscuous associations with several other monomer sequences. In that manner, SPACEHex will also pursue the reconstitution of hexameric platforms from orthogonal monomers based on de novo sequences.

After validating the structural design of final delivered hexamer platforms, their structural viability and compatibility with BMC shell environment will be evaluated in vitro and in vivo. Moreover, the potential of resulting platforms for synthetic biology will be tested using a tripartite enzymatic model.

Project coordination

Luis Garcia Alles (LABORATOIRE D'INGÉNIERIE DES SYSTÈMES BIOLOGIQUES ET DES PROCÉDÉS)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

JOLIOT Institut des sciences du vivant FRÉDÉRIC-JOLIOT
MIA INRA MIAT
LISBP LABORATOIRE D'INGÉNIERIE DES SYSTÈMES BIOLOGIQUES ET DES PROCÉDÉS
LISBP LABORATOIRE D'INGÉNIERIE DES SYSTÈMES BIOLOGIQUES ET DES PROCÉDÉS

Help of the ANR 461,443 euros
Beginning and duration of the scientific project: February 2020 - 42 Months

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