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

Projektinformationen

GUIDESIGINT

ID Finanzhilfevereinbarung: 702346

DOI

10.3030/702346

Projekt abgeschlossen

EK-Unterschriftsdatum 26 April 2016

Startdatum 1 Februar 2017

Enddatum 31 Januar 2019

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 159 460,80

EU-Beitrag

€ 159 460,80

Koordiniert durch

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)

Berichtszeitraum: 2017-02-01 bis 2019-01-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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

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