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.

Conformational states and recognition of amyloidogenic peptides of human insulin-degrading enzyme

“…Exemplary substrates of IDE are insulin and Aβ, which are critical for the development of type 2 diabetes mellitus (DM2) and Alzheimer's disease (AD), respectively. Genetic analyses strongly support functional roles of IDE in the clearance of insulin and Aβ (2,3). In humans, several single nucleotide polymorphisms at the IDE locus on human chromosome 10q are associated with DM2 and late-onset AD (5,6).…”

“…BK degradation is at least 20-fold higher (3,9,28). The door swing motion creates an ∼11-to 18-Å opening (Fig.…”

“…Protein-protease networks play a key role in proteostasis by ensuring proper protein function through protein turnovers (2). Amyloidogenic peptides, such as amyloid β (Aβ) and amylin, present a major challenge to proteostasis, because they can form toxic aggregates that impair diverse physiological functions and contribute to human diseases (3,4). Insulin-degrading enzyme (IDE), a Zn 2+ -metalloprotease, prefers to degrade amyloidogenic peptides to prevent the formation of amyloid fibrils (3).…”

The metalloendopeptidase gene Pitrm1 is regulated by hedgehog signaling in the developing mouse limb and is expressed in muscle progenitors

“…This family is characterised by an inverted zinc-binding motif HXXEH(X) 76 E (Rawlings and Barrett, 1995) and a number of its members are responsible for degrading short peptides by encapsulating substrates in a catalytic chamber (Malito et al, 2008). In vertebrates, there are several well-characterised M16 proteins that share structural similarity with Pitrm1, including Insulin Degrading Enzyme (IDE), NRD convertase, and Mitochondrial Processing Peptidase (MPP) (Fumagalli et al, 1998;Alper et al, 2006).…”

“…Of these, IDE has attracted the most research attention due to its ability to hydrolyse insulin (Kirschner and Goldberg, 1983), IGF-I, IGF-II (Misbin and Almira, 1989), and the Amyloid b-protein (Ab) (McDermott and Gibson, 1997). This suggests an association with several human disorders, particularly Type II diabetes and Alzheimer's disease (for a review, see Malito et al, 2008).…”