Structural dynamics of netrin signaling complexes

The Stetefeld lab has a long-standing interest in exploiting the structure-property relationship of key components in extracellular higher-order signaling complexes.  Starting with the very first high-resolution X-ray crystal structure of such a signaling component, the  study of the basement membrane protein laminin [1] helped to establish the field of structural biology of higher order matrix assemblies, and it has since become a standard reference in the field.

The lab expanded studies from individual domains over tandem arrangements towards signaling assemblies. For example, the unravelling of agrin-mediated neuromuscular junction formation [2,3] and the exploring of the effect of alternative mRNA splice inserts in muscular dystrophy [4,5] contributed significantly to a molecular understanding of underlying diseases. Other avenues of research included collagen assemblies via phage-based foldon systems [6,7], Cadherin super-assemblies [8] and integrin-snake venom lectin interactions [9].

Most recently, we have published work about Netrin-1 and its interaction with the dependence receptor UNC5 and Netrin-4 disrupting basement membrane networks [10,11]. Studies of these protein-protein networks are extremely important for the development of new therapeutic approaches in numerous cancers and neurodegenerative diseases. By applying AI-technology to this mostly transient protein-protein interaction networks it is envisioned to design and characterize specific mediators that allow for targeted apoptosis of specific cancer cells.

[1] Stetefeld et al. JMB, 1996 [2] Stetefeld et al. Nature Structural Biology, 2001 [3] Mascarenhas et al. EMBO J, 2003 [4] Stetefeld et al. Structure, 2004 [5] Stetefeld & Ruegg TIBS, 2005 [6] Stetefeld et al. Structure, 2004 [7] Boudko et al. JMB, 2004 [8] Haeussinger et al. EMBO J, 2004 [9] Eble et al. PlosBiol, 2017 [10] Grandin et al. Cancer Cell, 2016  [11] Reuten et al. Nature Communications, 2017