Molecular Basis for the Recognition and Cleavages of IGF-II, TGF-α, and Amylin by Human Insulin-Degrading Enzyme

Guo, Qi; Manolopoulou, Marika; Bian, Yao; Schilling, Alexander; Tang, Wei-Jen

doi:10.1016/j.jmb.2009.10.072

Cited by 81 publications

(171 citation statements)

References 46 publications

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“…Our previous structures of the IDE dimer in complex with Aβ and amylin reveal that regions of amyloidogenic peptides that form a β-strand in amyloids docks onto β6 within the IDE door subdomain to form an intermolecular, antiparallel β-sheet (Fig. 2C) (7,8). Because the door subdomain contains residues crucial for binding catalytic zinc and forming the catalytic cleft, the swing motion prevents IDE from hydrolyzing its substrates ( Fig.…”

Section: Roles Of Ide Swinging Door In Substrate Recognition and Rate Ofmentioning

confidence: 95%

“…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).…”

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confidence: 99%

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

McCord¹,

Liang²,

Dowdell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Insulin-degrading enzyme (IDE) selectively degrades the monomer of amyloidogenic peptides and contributes to clearance of amyloid β (Aβ). Thus, IDE retards the progression of Alzheimer's disease. IDE possesses an enclosed catalytic chamber that engulfs and degrades its peptide substrates; however, the molecular mechanism of IDE function, including substrate access to the chamber and recognition, remains elusive. Here, we captured a unique IDE conformation by using a synthetic antibody fragment as a crystallization chaperone. An unexpected displacement of a door subdomain creates an ∼18-Å opening to the chamber. This swinging-door mechanism permits the entry of short peptides into the catalytic chamber and disrupts the catalytic site within IDE door subdomain. Given the propensity of amyloidogenic peptides to convert into β-strands for their polymerization into amyloid fibrils, they also use such β-strands to stabilize the disrupted catalytic site resided at IDE door subdomain for their degradation by IDE. Thus, action of the swinging door allows IDE to recognize amyloidogenicity by substrate-induced stabilization of the IDE catalytic cleft. Small angle X-ray scattering (SAXS) analysis revealed that IDE exists as a mixture of closed and open states. These open states, which are distinct from the swinging door state, permit entry of larger substrates (e.g., Aβ, insulin) to the chamber and are preferred in solution. Mutational studies confirmed the critical roles of the door subdomain and hinge loop joining the N-and C-terminal halves of IDE for catalysis. Together, our data provide insights into the conformational changes of IDE that govern the selective destruction of amyloidogenic peptides.M16 metalloprotease | X-ray crystallography | substrate recognition P roteins in living organisms face acute and chronic challenges to their integrity, which necessitate proteostatic processes to protect their functions (1). 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). 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).Structural analyses have provided significant insights to substrate recognition and catalysis by IDE. IDE has two ∼50-kDa αβαβα N-terminal (IDE-N) and C-terminal (IDE-C) halves, which are linked by a short hinge loop...

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Section: Roles Of Ide Swinging Door In Substrate Recognition and Rate Ofmentioning

confidence: 95%

mentioning

confidence: 99%

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

McCord¹,

Liang²,

Dowdell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, yeast Ste24p and M16A proteases (Ste23p and Axl1p) cleave the a-factor precursor at different sites that are each distal from the CAAX motif, indicating that they can cleave non-prenylated regions of the same peptide, albeit at different locations (27,28,32). M16A proteases cleave a variety of small peptides, potentially up to ϳ80 amino acids in length (20,21,43). The maximum substrate size is limited by the volume of the M16A protease chamber (ϳ16,000 Å 3 ).…”

Section: Rce1p and Ste24p Differ In Theirmentioning

confidence: 99%

Ste24p Mediates Proteolysis of Both Isoprenylated and Non-prenylated Oligopeptides

Hildebrandt

Arachea

Wiener

et al. 2016

Journal of Biological Chemistry

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Rce1p and Ste24p are integral membrane proteins involved in the proteolytic maturation of isoprenylated proteins. Extensive published evidence indicates that Rce1p requires the isoprenyl moiety as an important substrate determinant. By contrast, we report that Ste24p can cleave both isoprenylated and non-prenylated substrates in vitro, indicating that the isoprenyl moiety is not required for substrate recognition. Steady-state enzyme kinetics are significantly different for prenylated versus nonprenylated substrates, strongly suggestive of a role for substratemembrane interaction in protease function. Mass spectroscopy analyses identify a cleavage preference at bonds where P1 is aliphatic in both isoprenylated and non-prenylated substrates, although this is not necessarily predictive. The identified cleavage sites are not at a fixed distance position relative to the C terminus. In this study, the substrates cleaved by Ste24p are based on known isoprenylated proteins (i.e. K-Ras4b and the yeast a-factor mating pheromone) and non-prenylated biological peptides (A␤ and insulin chains) that are known substrates of the M16A family of soluble zinc-dependent metalloproteases. These results establish that the substrate profile of Ste24p is broader than anticipated, being more similar to that of the M16A protease family than that of the Rce1p CAAX protease with which it has been functionally associated.

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“…An unexplained exception is Aβ 1-40 , the rate of which was increased by approximately twofold by phytic acid. In crystal structures of IDE with bound peptides (28,(35)(36)(37)(38)(39), larger substrates are seen to make contacts at both the active site and the distal site (which mediates activation by peptides). It is possible that activity is not stimulated for large peptides because they themselves activate in a manner similar to polyanions, particularly because their hydrolysis rates are often higher than those for small peptides.…”

Section: Ide Localization To Endosomes Involves the Polyanion-bindingmentioning

confidence: 99%

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

Song

Jang

Guo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact with the polyanion-binding site located on an inner chamber wall of the enzyme. InsPs activate IDE by up to ∼95-fold, affecting primarily V max . The extent of activation and binding affinity correlate with the number of phosphate groups on the inositol ring, with phosphate positional effects observed. IDE binds PtdInsPs from solution, immobilized on membranes, or presented in liposomes. Interaction with PtdInsPs, likely PtdIns(3)P, plays a role in localizing IDE to endosomes, where the enzyme reportedly encounters physiological substrates. Thus, InsPs and PtdInsPs can serve as endogenous modulators of IDE activity, as well as regulators of its intracellular spatial distribution.insulin-degrading enzyme | inositols | phosphatidylinositols | activation | subcellular localization I nsulin-degrading enzyme (IDE), also known as insulysin (EC 3.4.24.56), hydrolyzes a broad range of bioactive peptides in vitro, including angiotensin, glucagon, β-endorphin, amylin, and amyloid β peptides (Aβ), with the two most established in vivo substrates being insulin and Aβ. Evidence supporting a role for IDE in degrading insulin and Aβ in vivo includes associations of IDE gene variants with type 2 diabetes (1, 2) and Alzheimer's disease (3, 4), decreased clearance of the two peptides in IDE-deficient mice (5, 6), and antidiabetic activity produced by IDE inhibitors (7, 8), although some reports have questioned its role in insulin degradation (9, 10). In addition, IDE has been reported to have noncatalytic functions, such as acting as a receptor for varicella-zoster virus (11) and serving as a heat shock protein in stressed cells (12). IDE also modulates the activity of the proteasome (13), reportedly in conjunction with the retinoblastoma tumor-suppressor protein (14).We previously established that polyanions, such as free ATP and triphosphate, increase IDE activity by up to 100-fold toward a synthetic peptide substrate (15) and that ATP binds to a strongly electropositive inner surface of IDE that forms one-half of the substrate-binding chamber (16,17). Significantly, mutations in IDE that reduce its activation by polyanions also decrease its ability to rescue production of a mature yeast mating factor, indicating that activation by polyanions plays an important physiological role in cells (16). Physiological polyanionic activators of IDE have not yet been identified, however.Inositol phosphates (InsPs) are important intracellular second messengers generated by activation of many cell surface receptors (18,19). Phosphatidylinositol phosphates (PtdInsPs; phosphoinositides) participate in signaling and help define the identity of subcellular compartment...

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Molecular Basis for the Recognition and Cleavages of IGF-II, TGF-α, and Amylin by Human Insulin-Degrading Enzyme

Cited by 81 publications

References 46 publications

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

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

Ste24p Mediates Proteolysis of Both Isoprenylated and Non-prenylated Oligopeptides

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

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