Molecular Basis of Substrate Recognition and Degradation by Human Presequence Protease

King, John V. Lin; Liang, Wenyuan; Scherpelz, Kathryn P; Schilling, Alexander; Meredith, Stephen C.; Tang, Wei-Jen

doi:10.1016/j.str.2014.05.003

Cited by 47 publications

(68 citation statements)

References 58 publications

(105 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is due to the complicated factors involved in the progression of these two chronic diseases and redundant mechanisms for the clearance of these peptides [3, 24, 34, 37]. For example, several proteases such as IDE, neprilysin, endothelin converting enzyme-1, and presequence protease, are involved in Aβ clearance [3, 38–40]. Nevertheless, several single nucleotide polymorphisms (SNPs) in non-coding regions of the human IDE gene on chromosome 10q are associated with T2DM [41–44].…”

Section: Ide Substrates and Functionsmentioning

confidence: 99%

Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus

Tang

2016

Trends in Endocrinology & Metabolism

Self Cite

127

View full text Add to dashboard Cite

Insulin degrading enzyme (IDE) selectively degrades peptides such as insulin, amylin, and amyloid β (Aβ) that form toxic aggregates, to maintain proteostasis. IDE defects are linked to the development of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). Structural and biochemical analyses revealed the molecular basis for IDE-mediated destruction of amyloidogenic peptides and this information has been exploited to develop promising inhibitors of IDE to improve glucose homeostasis. However, the inhibition of IDE can also lead to glucose intolerance. This review focuses on recent advances regarding our understanding of the structure and function of IDE and the discovery of IDE inhibitor, as well as challenges in developing IDE-based therapy for human diseases, particularly T2DM.

show abstract

Section: Ide Substrates and Functionsmentioning

confidence: 99%

Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus

Tang

2016

Trends in Endocrinology & Metabolism

Self Cite

127

View full text Add to dashboard Cite

show abstract

“…6). A 2 Å resolution structure of hPreP has recently been published [27] and was deposited in the Protein Data Bank as 4L3T. We should point out that the hPreP in this structure was modified, with some lysine residues derivatized to N-dimethyl-lysine and some cysteine residues derivatized to S-(dimethylarsenic)-cysteine.…”

Section: Discussionmentioning

confidence: 99%

“…Upper panel . Overview of the hPreP structure [27] (4L3T, pale green) with the residues composing the active site shown in red and the hinge region colored in yellow. The internal cavity in hPreP is filled with a gray mesh, and the dashed line shows the proposed path of opening.…”

Section: Figmentioning

confidence: 99%

Mechanism of oxidative inactivation of human presequence protease by hydrogen peroxide

Chen

Teixeira

Glaser

et al. 2014

Free Radical Biology and Medicine

View full text Add to dashboard Cite

The mitochondrial presequence protease (PreP) is a member of the pitrilysin class of metalloproteases. It degrades the mitochondrial targeting presequences of mitochondria-localized proteins as well as unstructured peptides such as amyloid-β-peptide. The specific activity of PreP is reduced in Alzheimer patients and animal models of Alzheimer disease. The loss of activity can be mimicked in vitro by exposure to oxidizing conditions, and indirect evidence suggested that inactivation was due to methionine oxidation. We performed peptide mapping analyses to elucidate the mechanism of inactivation. None of the 24 methionine residues in recombinant human PreP was oxidized. We present evidence that inactivation was due to oxidation of cysteine residues and consequent oligomerization through intermolecular disulfide bonds. The most susceptible cysteine residues to oxidation are Cys34, Cys112, and Cys119. Most, but not all, of the activity loss is restored by the reducing agent, dithiothreitol. These findings elucidate a redox mechanism for regulation of PreP and also provide a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.

show abstract

“…Other research groups have also utilized the O-acyl isopeptide for a wide range of Aβ studies. [54][55][56][57][58][59][60][61][62] Moreover, the O-acyl isopeptide of amylin, a 37-residue amyloid peptide associated with type II diabetes mellitus, was reported. 24,63) Thus, the effective preparation of Aβ1-42 via the O-acyl isopeptide allowed us to conduct medicinal chemistry studies focusing on the aggregation of Aβ1-42.…”

Section: O-acyl Isopeptide Of Aβ1-42mentioning

confidence: 99%

Medicinal Chemistry Focusing on Aggregation of Amyloid-β

Sohma

2016

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

The aggregation of peptides/proteins is intimately related to a number of human diseases. More than 20 have been identified which aggregate into fibrils containing extensive β-sheet structures, and species generated in the aggregation processes (i.e., oligomers and fibrils) contribute to disease development. Amyloid-β peptide (designated Aβ), related to Alzheimer's disease (AD), is the representative example. The intensive aggregation property of Aβ also leads to difficulty in its synthesis. To improve the synthetic problem, we developed an O-acyl isopeptide of Aβ1-42, in which the N-acyl linkage (amide bond) of Ser 26 was replaced with an O-acyl linkage (ester bond) at the side chain. The O-acyl isopeptide demonstrated markedly higher watersolubility than that of Aβ1-42, while it quickly converted to intact monomer Aβ1-42 via an O-to-N acyl rearrangement under physiological conditions. Inhibition of the pathogenic aggregation of Aβ1-42 might be a therapeutic strategy for curing AD. We succeeded in the rational design and identification of a small molecule aggregation inhibitor based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-]. Moreover, the inhibition of Aβ aggregation was achieved via oxygenation (i.e., incorporation of oxygen atoms to Aβ) using an artificial catalyst. We identified a selective, cell-compatible photo-oxygenation catalyst of Aβ, a flavin catalyst attached to an Aβ-binding peptide, which markedly decreased the aggregation potency and neurotoxicity of Aβ.

show abstract

Molecular Basis of Substrate Recognition and Degradation by Human Presequence Protease

Cited by 47 publications

References 58 publications

Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus

Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus

Mechanism of oxidative inactivation of human presequence protease by hydrogen peroxide

Medicinal Chemistry Focusing on Aggregation of Amyloid-β

Contact Info

Product

Resources

About