Amyloid β-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin

Abstract.

The accumulation of aggregates of amyloidogenic peptides is associated with numerous human diseases. One well studied example is the association between deposition of amyloid β (Aβ) and Alzheimer’s disease. Insulin degrading enzyme and neprilysin are involved in the clearance of Aβ, and presequence peptidase is suggested to play a role in the degradation of mitochondrial Aβ. Recent structural analyses reveal that these three peptidases contain a catalytic chamber (crypt) that selectively encapsulates and cleaves amyloidogenic peptides, hence the name cryptidase. The substrate selectivity of these cryptidases is determined by the size and charge distribution of their crypt as well as the conformational flexibility of substrates. The interaction of Aβ with the catalytic core of these cryptidases is controlled by conformational changes that make the catalytic chambers accessible for Aβ binding. These new structural and biochemical insights into cryptidases provide potential therapeutic strategies for the control of Aβ clearance.