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Defining the role of Arp2/3 complex diversity at multiple scales of biology

Project description

A miniature 'tree of life' inside our cells reveals the meaning of its intricacies

Cells are highly active and versatile structures capable of changing shape and moving both in place and within the body. Cell division and migration during development is only one of a myriad of examples. Providing mechanical support and assisting in movement is the cytoskeleton, made of filament-like proteins. Actin is one of these, and the actin-related protein 2/3 (Arp2/3) complex is largely responsible for the creation of an elaborate and branched actin network; it nucleates branched filaments by binding to existing filaments and promoting the growth of new branches. It turns out that the Arp2/3 complex is not one but can exist in eight different combinations of subunits, with differences having dramatic impact on actin networks. The EU-funded ArpComplexity project is untangling all these subunits and their combinations, both structurally and functionally, to better understand what they do, how they do it and why.

Objective

The actin cytoskeleton of the cell is critical for the complex, integrated processes associated with development, operation and sustainability of the human body. The Arp2/3 complex consisting of seven protein subunits is essential to stimulate dynamic branched actin networks needed for multiple cellular processes. The Arp2/3 complex has always been considered as a single entity, but in humans and other mammals, three of the Arp2/3 complex subunits are encoded by two isoforms, thus allowing the formation of eight distinct Arp2/3 complexes. The Way lab has shown that Arp2/3 subunit composition dramatically affects the formation and stability of branched actin networks. The Way and Gomes labs have shown how specific Arp2/3 isoforms are essential for muscle development.

Our synergistic, high-risk, high-gain goal is to define the role of Arp2/3 complex diversity at three hierarchies of biology:

1. Molecular basis of Arp2/3 diversification
With purified isoform-specific complexes we will perform cryo-electron microscopy and single molecule fluorescence microscopy to reveal the structural variations and influence of Arp2/3 diversity on actin networks in vitro.

2. Cellular function of different Arp2/3 complexes
With cells expressing specific Arp2/3 isoforms, we will use quantitative live cell imaging and cryoelectron tomography to reveal the dependence of cellular actin networks on Arp2/3 diversity and its functional consequences.

3. Developmental and physiological role of individual Arp2/3 complexes.
With genetically modified cultured myofibers and transgenic mice, we will use an array of imaging approaches to reveal the contribution of different Arp2/3 family members to muscle development, structure and physiology.

Our interdisciplinary plan builds on the strengths of our three labs, takes advantage of unique reagents and powerful model systems, and will allow us to determine how Arp2/3 diversity contributes to biological complexity at multiple scales.

Host institution

THE FRANCIS CRICK INSTITUTE LIMITED
Net EU contribution
€ 4 148 087,00
Address
1 MIDLAND ROAD
NW1 1AT London
United Kingdom

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Region
London Inner London — West Camden and City of London
Activity type
Research Organisations
Links
Total cost
€ 4 148 087,00

Beneficiaries (3)