Structural Basis for Selective Proteolysis of ADAM10 Substrates at Membrane-Proximal Sites
Lipper, C. H.; Egan, E. D.; Gabriel, K.-H.; Blacklow, S. C.
Show abstract
The endopeptidase ADAM10 is a critical catalyst for regulated proteolysis of key drivers of mammalian development and physiology, and for non-amyloidogenic cleavage of the Alzheimers precursor protein as the primary -secretase. ADAM10 function in vivo requires formation of a complex with a C8-tetraspanin protein, with different ADAM10-C8-tetraspanin complexes having distinct substrate selectivity, yet the basis for such selectivity remains elusive. We present here a cryo-EM structure of a vFab-ADAM10-Tspan15 complex, which shows that Tspan15 binding relieves ADAM10 autoinhibition and positions the enzyme active site about 20 [A] from the plasma membrane for membrane-proximal substrate cleavage. Cell-based assays of N-cadherin shedding establish that the positioning of the active site by the interface between the ADAM10 catalytic domain and the bound tetraspanin influences selection of the preferred cleavage site. Together, these studies reveal the molecular mechanism underlying selective ADAM10 proteolysis at membrane-proximal sites and offer a roadmap for its modulation in disease.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes 96%
- Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3. 95%
- Molecular and Structural Basis of Olfactory Sensory Neuron Coalescence by Kirrel Receptors 95%
Similar papers in this journal
- Structure of the teneurin-latrophilin complex: Alternative splicing controls synapse specificity by a novel mechanism 96%
- Alternative splicing controls teneurin-3 compact dimer formation for neuronalrecognition 95%
- Structure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.