Title : Structural characterization of the
ectodomain of a
disintegrin and
metalloproteinase-22 (
ADAM22 ), a neural adhesion
receptor instead of
metalloproteinase : insights on ADAM function
Abstract :
- ADAMs (a disintegrin and metalloproteinases ) are a family of multidomain transmembrane glycoproteins with diverse roles in physiology and diseases, with several members being drug targets for cancer and inflammation therapies
- The spatial organization of the ADAM extracellular segment and its influence on the function of ADAMs have been unclear
- Although most members of the ADAM family are active zinc metalloproteinases , 8 of 21 ADAMs lack functional metalloproteinase domains and are implicated in protein-protein interactions instead of membrane protein ectodomain shedding
- One of such non-proteinase ADAMs, ADAM22 , acts as a receptor on the surface of the postsynaptic neuron to regulate synaptic signal transmission
- The crystal structure of the full ectodomain of mature human ADAM22 shows that it is a compact four-leaf clover with the metalloproteinase-like domain held in the concave face of a rigid module formed by the disintegrin , cysteine-rich, and epidermal growth factor-like domains
- The loss of metalloproteinase activity is ensured by the absence of critical catalytic residues , the filling of the substrate groove, and the steric hindrance by the cysteine-rich domain
- The structure, combined with calorimetric experiments, suggests distinct roles of three putative calcium ions bound to ADAM22 , with one in the metalloproteinase-like domain being regulatory and two in the disintegrin domain being structural
- The metalloproteinase-like domain contacts the rest of ADAM22 with discontinuous, hydrophilic, and poorly complemented interactions, suggesting the possibility of modular movement of ADAM22 and other ADAMs
- The ADAM22 structure provides a framework for understanding how different ADAMs exert their adhesive function and shedding activities