Pitrilysins/Inverzincins

Maskos, K.

doi:10.1002/0470028637.met034

Cited by 3 publications

(4 citation statements)

References 72 publications

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“…Recent structural analysis revealed that human IDE consists of two roughly equally sized N- and C-terminal domains (IDE-N and IDE-C)3. IDE-N and IDE-C are homologous to each other and have an αβαβα-roll structure, shared among proteases within the M16 family, which include mitochondrial processing peptidase, pitrilysin, and mitochondrial presequence peptidase5; 6; 7. IDE-N and IDE-C are joined by an extended 28 amino acid loop, and together they form an enclosed chamber to selectively enclose and cleave certain peptides.…”

Section: Introductionmentioning

confidence: 99%

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

Guo

Manolopoulou

Bian

et al. 2010

Journal of Molecular Biology

160

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Insulin-degrading enzyme (IDE) is involved in the clearance of many bioactive peptide substrates, including insulin and amyloid-β (Aβ), peptides vital to the development of diabetes and Alzheimer's disease, respectively. IDE can also rapidly degrade hormones that are held together by intramolecular disulfide bond(s) without their reduction. Furthermore, IDE exhibits a remarkable ability to preferentially degrade structurally similar peptides such as the selective degradation of insulingrowth factor-II (IGF-II) and transforming growth factor-α (TGF-α) over IGF-I and epidermal growth factor (EGF), respectively. Here, we used high accuracy mass spectrometry to identify the cleavage sites of human IGF-II, TGF-α, amylin, reduced amylin, and Aβ by human IDE. We also determined the structures of human IDE-IGF-II and IDE-TGF-α at 2.3 Å and IDE-amylin at 2.9 Å. We found that IDE cleaves its substrates at multiple sites in a biased stochastic manner. Furthermore, the presence of a disulfide bond in amylin allows IDE to cut at an additional site in the middle of the peptide (aa 18-19). Our amylin-bound IDE structure offers insight into how the structural constraint from a disulfide bond in amylin can alter IDE cleavage sites. Together with NMR structures of amylin and the IGF and EGF families, our work also reveals the structural basis of how the high dipole moment of substrates complements the charge distribution of the IDE catalytic chamber for the substrate selectivity. In addition, we show how the ability of substrates to properly anchor their Nterminus to the exosite of IDE and undergo a conformational switch upon binding to the catalytic chamber of IDE can also contribute to the selective degradation of structurally related growth factors.

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Section: Introductionmentioning

confidence: 99%

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

Guo

Manolopoulou

Bian

et al. 2010

Journal of Molecular Biology

160

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“…Thus, IDE needs to undergo a significant conformational change from the open state, which can accept substrate, to the closed state for proper substrate recognition and catalysis. The structural comparison of substrate-bound IDE with substrate-free Escherichia coli pitrilysin (PDB accession code 1Q2L) reveals how repositioning between IDE-N and IDE-C can lead to the open state, which allows substrate to access the catalytic cavity 16 ( Fig. 3b and Supplementary Fig.…”

mentioning

confidence: 99%

“…10). Similar to IDE, MPP also uses the exosite for substrate recognition 16,27,28 . The catalytic chamber of MPP stays open, however, whereas IDE has a buried catalytic site in the structure and access to this chamber is kinetically controlled by the closed-open conformational switch.…”

mentioning

confidence: 99%

Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism

Shen

Joachimiak

Rosner

et al. 2006

Nature

333

776

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Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid-beta (refs 1-3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-beta, whereas enhanced IDE activity effectively reduces brain amyloid-beta (refs 4-7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form beta-sheets with two discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations.

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“…In fact, they act cooperatively to remove the presequences from the precursor proteins. In particular, α-MPP participates in the substrate recognition through many binding sites negatively charged and present in its C-terminal domain − and a highly conserved region rich in glycine and histidine residues, ,,, and β-MPP is the catalytic subunit …”

Section: Introductionmentioning

confidence: 99%

A Proposal for Mitochondrial Processing Peptidase Catalytic Mechanism

et al. 2011

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The reaction mechanism of the Mitochondrial Processing Peptidase enzyme (MPP) was investigated by using hybrid density functional theory. This enzyme removes the NH(2)-terminal targeting signals of nuclear-encoded mitochondrial protein precursors in the mitochondrial matrix. The catalytic process was studied using a model for the active site consisting of 161 atoms locating all the stationary points on the potential energy curve and determining the main energetic, structural, and electronic features that drive the catalysis. Despite the differences between the B3LYP and MPWB1K descriptions, it is possible hypothesize that the rate-limiting step of the reaction is most likely the nucleophilic attack of zinc-bound hydroxide to a carbonyl carbon of the substrate. The results allowed assignment of the proper roles to some active site residues in this mechanism.

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Pitrilysins/Inverzincins

Cited by 3 publications

References 72 publications

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

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

Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism

A Proposal for Mitochondrial Processing Peptidase Catalytic Mechanism

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