Insulin-degrading Enzyme Modulates the Natriuretic Peptide-mediated Signaling Response

Abstract

The natriuretic peptides (NPs), 2 mainly atrial (ANP), Btype (BNP), and C-type natriuretic peptides (CNP), play key roles in many cardiovascular functions (1). Their diuretic, natriuretic, and vasodilatory properties have been developed as therapeutic strategies for human cardiovascular diseases (2). The actions of NPs are mediated through binding and signal transduction of three natriuretic peptide receptors (NPR). NPR-A and NPR-B have guanylyl cyclase activity that raises intracellular cGMP levels. Effects of these receptors are mediated by the preferential binding of ANP and BNP to NPR-A and by that of CNP to NPR-B. NPR-C is a non-guanylyl cyclase receptor. In addition to its role in the clearance of NPs, NPR-C also can transmit signals via heterotrimeric G protein, G i (3, 4).NPs have a short half-life and their circulation levels are tightly controlled (5, 6). In addition to the regulation of NPs by gene transcription, secretion, and NPR-C mediated clearance, NP maturation and breakdown by multiple proteases are also key in NP regulation. For example, active NPs are converted from pro-NPs by furin, corin, and likely, by other proteases (7,8). Active NPs are postulated to be proteolytically inactivated by a membrane-bound metalloprotease, neprilysin (NEP) (9 -12). However, growing evidence propose the role of other proteases in the clearance of NPs. Meprin A is shown to be involved in the initial N-terminal cleavage of BNP and meprin A and NEP are thought to work together in the clearance of BNP (13). In addition, insulin-degrading enzyme (IDE) and DPP-IV have been shown to cleave NPs in vitro (14 -16) However, the functional consequence in the cleavage of NPs by these two proteases in the cellular setting remains unknown.IDE is a ubiquitously expressed zinc-metalloprotease that is involved in the clearance of insulin and amyloid-␤ (A␤), peptides implicated in the pathogenesis of diabetes and Alzheimer's disease, respectively (17-19). We have recently solved the structure of human IDE in complex with various substrates and elucidated the molecular basis for the recognition and selective degradation of substrates by IDE (20 -22). Our structures reveal that IDE uses a sizable catalytic chamber to entrap, unfold, and degrade insulin, A␤, and other substrates. IDE recognizes its substrates mainly based on their tertiary structures. The size, dipole moment, structure flexibility, and location of the N-terminal end of the substrates are key factors for the selectivity of IDE.IDE was shown to degrade ANP and BNP (15,16), however it was never established whether the cleavages of ANP and * This work was supported, in whole or in part, by National Institutes of Health Grants GM81539 (to W.-J. T.), F32 GM87093 (to L. A. R.), 5T32HL07237-33 (to T. F.), and R21HL093402-01 (to L. R. P.). The atomic coordinates and structure factors (codes 3N56 and 3N57) CNP, C-type natriuretic peptide; DNP, dendroaspis natriuretic peptide; fsANP, frameshift mutant atrial natriuretic peptide; NPR-A, natriuretic peptide receptor-A; NPR-B,...

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

“…This agrees with biochemical data that IDE R767A exists mostly as a monomer, but some dimers can still form (Fig. 4C) (10). IDE S132C/E817C introduces a disulfide bond to lock IDE D1 and D4 together, which only becomes active under reducing conditions (7).…”

“…S1) (3, 7). IDE uses the size, shape, and charge distribution of its chamber (∼13,000 Å 3 ) to selectively engulf structurally diverse peptides, such as insulin, Aβ, tumor growth factor-α, macrophage inflammatory protein-1α (MIP-1α), natriuretic peptides, and amylin (7)(8)(9)(10)(11). IDE substrates are presumably unraveled inside the catalytic chamber and then stochastically cleaved in regions that have a high propensity to convert into a β-strand for the formation of intermolecular cross-β sheets, the fundamental structural element of amyloid fibrils (7)(8)(9).…”

Natriuretic Peptides and Analytical Barriers

“…The variety of such fragments is believed to be the result of proteolysis by dipeptidyl peptidase IV (DPP IV), which forms BNP 3-32 and neprilysin (NEP), which forms BNP 5-32. BNP can also be proteolyzed by insulindegrading enzyme (IDE), but not by NEP and IDE implying that another enzyme is involved in cleavage (25 ). BNP 4 -32 may be the result of corin activity (21 ).…”

Atrial Natriuretic Peptide ― Old But New Therapeutic in Cardiovascular Diseases ―

“…62 Ralat et al reported that IDE rapidly cleaves ANP, so inhibition of IDE expression may enhance the action of GC-A by prolonging the half-life of ANP. 63 Inhibition of IDE in CVD has not investigated yet, but IDE inhibition may be a good therapeutic for type II diabetes and Alzheimer's disease, as has been reported. 64, 65 For example, Maianti et al performed a chemical and biochemical survey of a DNAtemplate library and found an optimal small-molecule inhibitor, 6bk IDE inhibitor.…”