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

Información del proyecto

GUIDESIGINT

Identificador del acuerdo de subvención: 702346

DOI

10.3030/702346

Proyecto cerrado

Fecha de la firma de la CE 26 Abril 2016

Fecha de inicio 1 Febrero 2017

Fecha de finalización 31 Enero 2019

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 159 460,80

Aportación de la UE

€ 159 460,80

Coordinado por

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)

Período documentado: 2017-02-01 hasta 2019-01-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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

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