Competitive assembly dynamics of the DCC receptor with its guidance cues integrates signals for cellular steering

Informations projet

GUIDESIGINT

N° de convention de subvention: 702346

DOI

10.3030/702346

Projet clôturé

Date de signature de la CE 26 Avril 2016

Date de début 1 Février 2017

Date de fin 31 Janvier 2019

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 159 460,80

Contribution de l’UE

€ 159 460,80

Coordonné par

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Germany

Periodic Reporting for period 1 - GUIDESIGINT (Competitive assembly dynamics of the DCC receptor with its guidance cues integrates signals for cellular steering)

Période du rapport: 2017-02-01 au 2019-01-31

Résumé du contexte et des objectifs généraux du projet

The development of human nerve and blood vessel networks is a complex process. In part, it relies on a molecular communication hub involving the signaling protein netrin, which allows growing cells to orient themselves within a developing tissue and direct their migration patterns. A mechanistic depiction of this process underpins an understanding of our own nature, and propels our capacity for medical intervention in neural repair and cancer treatments. In this project, we explored the biophysical relationships between netrin and its binding partners as a molecular basis of cellular communication. Our ultimate goal is to translate molecular-scale discoveries to animal models, and finally to human medicine.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The human protein netrin contains binding sites for multiple partners in a complex interaction network. In particular, netrin assembles two cell receptor proteins in alternative configurations that have opposing effects on cell growth and migration patterns. We first approached this puzzle by molecular dissection, in which the role of each of three binding sites within netrin was independently clarified. Next, we discovered an additional cofactor that redistributes netrin binding propensities, acting as a molecular switch for interaction. Interestingly, this natural cofactor can also be truncated to small drug-like compounds with high potency. We are currently validating these molecular-scale biological findings in a mouse model, and in parallel determining the potential of the truncated cofactor to be used in a therapeutic setting.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Beyond the state of the art in fundamental neurobiological research, we are considering a patent application.

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