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Biophysical and structural studies on Wnt-regulatory complexes of LRP5/6, Dickkopf and Kremen

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Molecular locks and keys in cancer

Dysfunction in regulation of extracellular signalling pathways plays a role in cancer. EU-funded scientists have provided a high-resolution view of cell surface molecular interactions that could be potential therapy targets.

Health

A plethora of intercellular signalling molecules and cell surface receptors work together to control development and function. Disruption of these signals is implicated in developmental defects, degenerative diseases and cancer. EU-funded scientists carried out detailed studies of the regulation of one family of extracellular signalling molecules within the scope of the project 'Biophysical and structural studies on Wnt-regulatory complexes of LRP5/6, Dickkopf and Kremen' (DICKKOPF). The Wnt family of secretory glycolipoproteins (proteins functionalised with sugars and lipids) plays critical roles in embryonic development and tissue homeostasis. Wnt glycolipoproteins bind to cell surface co-receptors (low-density lipoprotein receptor-related protein 5 and 6 co-receptors (LRP5/6)) that are potential carcinogens. Wnt functional activity is highly regulated. Dickkopf proteins (Dkk) compete with Wnt for the co-receptors and thus their presence minimises Wnt functional activity. A second class of cell surface receptors (Kremen 1 and 2) amplify Dkk function and thus increase Wnt inhibition. Another pathway of secreted proteins (R-spondin) and transmembrane receptors as well as a secreted enzyme (Notum) increase Wnt functional activity. DICKKOPF researchers employed a wide range of advanced experimental methods. They studied complex formation, including affinities and kinetics, as well as the actual structures and structural changes of isolated complex components. Regarding the Wnt inhibition pathway, the team resolved the structure of the extracellular Kremen domain. In combination with published structures of LRP and Dkk, scientists were able to define a structure in which Dkk is sandwiched between Kremen and LRP. Scientists were also able to identify several pieces of the puzzle in the second and less-studied amplification pathway. They crystallised a fragment of an R-spondin similar in structure to parts of cell surface receptors and having signalling capability. Additional experiments suggested the structure and function of the R-spondin proteins. The team also solved the structure of the human Notum enzyme at high resolution and provided insight regarding heparin binding. DICKKOPF outcomes provide important information regarding the structural and functional mechanisms of Wnt regulation at the cell surface. Given the strong ties of dysfunctions in this signalling pathway and cancer development, scientists have opened a window on potential new targets for cancer therapy.

Keywords

Cancer, extracellular, signalling pathways, cell surface, molecular interactions, therapy targets, receptors, Wnt, regulatory complexes, LRP5/6, Dickkopf, Kremen, Dkk, R-spondin, Notum

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