The cell adhesion GPCR latrophilin 1 (LPHN1) and a major class of presynaptic organizers, neurexins (NRXs), were both first discovered as receptors of the potent neurotoxin α-Latrotoxin (α-LTX) from the venom of the black widow spider Latrodectus. Both receptors were suggested later to interact with each other, forming an intriguing intercellular adhesion complex. LPHNs and NRXNS, contribute to the aetiology of attention deficit and autism spectrum disorders, which in turn are often linked to impairments of synaptic interfaces.
We recently reveraled the overall 3D architecture of Latrotoxin, but mechanistic insights into the interactions of the toxin with these receptors, which could hold the key to future applications, are still lacking. In this CRC project, we aim to provide the necessary mechanistic insights into the complex interplay between NRX, LPHN1 and LTX and shed light how the toxin highjacks the respective presynaptic regulatory mechanisms. This will be done by studying the respective complexes both in vitro and in situ using cryoEM and a combination of biophysical and biochemical techniques.
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- Pöpsel S, Sprengel A, Sacca B, Kaschani F, Kaiser M, Gatsogiannis C, Raunser S, Clausen T, Ehrmann M. (2015). Determinants of amyloid fibril degradation by the PDZ protease HTRA1. Nature Chem Biol. 11:862–869.
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