FNIII-STRUCTURES · Investigation of structural interactions of Fibronectin type III domains
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-09-01 → 2009-06-30
- EU contribution
- €160,180
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - FNIII-STRUCTURES (Investigation of structural interactions of Fibronectin type III domains)
Our work focussed on human fibronectin, a major component of the matrix that holds cells together in tissues. Fibronectin is important for an array of processes, including embryo development, wound healing and also cancer metastasis. We proposed to study how fibronectin molecules come together, in a process known as fibrillogenesis, to form this matrix. Important unanswered questions in the field were related to how the matrix creation was regulated, how fibronectin transmitted signals to cells and how it interacted with other components of this matrix. We studied these questions over a two year period. We found that the conformation of fibronectin, i.e. the way this molecule looked like in space, played an important role in controlling the various activities. We showed that altering specific aspects of this conformation, for example transiting between a compact and an extended fibronectin state, led to the initial steps of matrix creation as well as to signals for cells to migrate. Cell mobility also depended on the consistency and properties of the matrix surrounding them, e.g. on how dense the matrix was and whether cells could cleave their way through. We showed conclusively that fibronectin interacted with specific sites on collagen, which was a biomolecule comprising over 25 % of the body protein content by weight. Collagen was also an important matrix component; hence this interaction with fibronectin had clear implications on the matrix structure. We continued working on better identifying this interaction in order to shed light on how cells migrated.
Data: CORDIS, © European Union
Project objective
Fibronectin (FN) is a multidomain extracellular matrix protein also present in soluble form in blood and tissue fluids. Soluble dimeric FN assembles on the cell surface into a supermolecular structure known as the FN matrix, which appears during embryonic development and wound healing. The monomeric subunit of FN is composed of three types of repeating domains, named type I, II and III. Recent reports suggest that FN type III domain unfolding is important for regulation of the FN matrix formation, and that it could also be the basis of the FN elasticity. Of particular interest are the first three type III domains (1FNIII, 2FNIII and 3FNIII), which harbour FN self-association sites and have been shown to be necessary in part for fibril formation. Anastellin, a truncated derivative of the 1FNIII domain has also be shown to be capable of inducing formation of an FN matrix-like supermolecular structure. Recent studies in our laboratory have shown that 1FNIII and 2FNIII are connected through a long amino acid linker, thus allowing significant flexibility in the relative orientation of 1FNIII and 2FNIII. In contrast, all other type III domains are connected through small linkers, which restrict the flexibility of relative orientations between adjacent domains. Preliminary results confirm the presence of an interdomain interaction between 1FNIII and 2FNIII. Here we propose to use high resolution NMR techniques to investigate the structural interactions between the first three type III domains of FN. Our aim is to deter mine the mode of association between these domains in various combinations, as well as the resulting three dimensional structures. In addition, the effect of anastellin on the possible interactions between these three domains will be studied. We expect that these structural studies will provide significant insight into the FN polymerization process and mechanical properties.
Original text from CORDIS.
Participants
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OXFORDCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union