Insulin degrading enzyme

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Insulin-degrading enzyme
PDB rendering based on 2g47.
Available structures: 2g47, 2g48, 2g49, 2g54, 2g56
Identifiers
Symbol(s) IDE; FLJ35968; INSULYSIN
External IDs OMIM: 146680 MGI: 96412 HomoloGene: 3645
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 3416 15925
Ensembl ENSG00000119912 ENSMUSG00000056999
Uniprot P14735 Q8CGB9
Refseq NM_004969 (mRNA)
NP_004960 (protein)		 XM_974712 (mRNA)
XP_979806 (protein)
Location Chr 10: 94.2 - 94.32 Mb Chr 19: 37.34 - 37.4 Mb
Pubmed search [1] [2]

Insulin-degrading enzyme, also known as IDE, is a human gene.[1]

Insulin Degrading Enzyme (IDE) is a large zinc-binding protease of the M16A metalloprotease subfamily known to cleave multiple short polypeptides that vary considerably in sequence. Known alternatively as insulysin or insulin protease, IDE was first identified by its ability to degrade the B chain of the hormone insulin. This activity was observed over fifty years ago,[2] though the enzyme specifically responsible for B chain cleavage was identified more recently.[3] This discovery revealed considerable amino acid sequence homology between IDE and the previously characterized bacterial protease pitrilysin, suggesting a common proteolytic mechanism. IDE, which migrates at 110 kDa during gel electrophoresis under denaturing conditions, has since been shown to have additional substrates, including the signaling peptides glucagon, TGF alpha, and β-endorphin.[4]

Contents

[edit] IDE and Alzheimer's Disease

Considerable interest in IDE has been stimulated due to the discovery that IDE can degrade amyloid beta (Aβ), a peptide implicated in the pathogenesis of Alzheimer’s disease.[5] The underlying cause or causes of the disease are unclear, though the primary neuropathology observed is the formation of amyloid plaques and neurofibrillary tangles. One hypothesized mechanism of disease, called the amyloid hypothesis, suggests that the causative agent is the hydrophobic peptide Aβ, which forms quaternary structures that, by an unclear mechanism, cause neuronal death. Aβ is a byproduct generated as the result of proteolytic processing of the amyloid precursor protein (APP) by proteases referred to as the β and γ secretases. The physiological role of this processing is unclear, though it may play a role in nervous system development.[6]

Numerous in vitro and in vivo studies have shown correlations between IDE, Aβ degradation, and Alzheimer’s disease. Mice engineered to lack both alleles of the IDE gene exhibit a 50% decrease in Aβ degradation, resulting in cerebral accumulation of Aβ.[7] Studies of genetically inherited forms of Alzheimer’s show reduction in both IDE expression[8] and catalytic activity[9] among affected individuals. Despite the evident role of IDE in disease, relatively little is known about its physiological functions. These may be diverse, as IDE has been localized to several locations, including the cytosol, peroxisomes, endosomes, proteasome complexes,[10] and the surface of cerebrovascular endothelial cells.[11]

[edit] IDE Structure and Function

Structural studies of IDE by Shen et al.[12] have provided insight into the functional mechanisms of the protease. Reminiscent of the previously determined structure of the bacterial protease pitrilysin, the IDE crystal structure reveals defined N and C terminal units that form a proteolytic chamber containing the zinc-binding active site. In addition, it appears that IDE can exist in two conformations: an open conformation, in which substrates can access the active site, and a closed state, in which the active site is contained within the chamber formed by the two concave domains. Targeted mutations that prevent the closed conformation result in a 40-fold increase in catalytic activity. Based upon this observation, it has been proposed that a possible therapeutic approach to Alzheimer’s might involve shifting the conformational preference of IDE to the open state, and thus increasing Aβ degradation, preventing aggregation, and, ideally, preventing the neuronal loss that leads to disease symptoms.

[edit] References

  1. ^ Entrez Gene: IDE insulin-degrading enzyme.
  2. ^ Mirsky IA, Broh-Kahn RH (1949). "The inactivation of insulin by tissue extracts. I. The distribution and properties of insulin inactivating extracts (insulinase)". Arch Biochem. 20: 1–9. 
  3. ^ Affholter JA, Fried VA, Roth RA (1988). "Human insulin-degrading enzyme shares structural and functional homologies with E. coli protease III". Science 242 (4884): 1415–8. doi:10.1126/science.3059494. PMID 3059494. 
  4. ^ Wang DS, Dickson DW, Malter JS (2006). "beta-Amyloid Degradation and Alzheimer's Disease". J. Biomed. Biotechnol. 2006 (3): 58406. doi:10.1155/JBB/2006/58406. PMID 17047308. 
  5. ^ Kurochkin IV, Goto S (1994). "Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme". FEBS Lett. 345 (1): 33–7. doi:10.1016/0014-5793(94)00387-4. PMID 8194595. 
  6. ^ Kerr ML, Small DH (2005). "Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development". J. Neurosci. Res. 80 (2): 151–9. doi:10.1002/jnr.20408. PMID 15672415. 
  7. ^ Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003). "Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo". Proc. Natl. Acad. Sci. U.S.A. 100 (7): 4162–7. doi:10.1073/pnas.0230450100. PMID 12634421. 
  8. ^ Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin LW, Kovacina KS, Craft S (2003). "Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele". Am. J. Pathol. 162 (1): 313–9. PMID 12507914. 
  9. ^ Kim M, Hersh LB, Leissring MA, Ingelsson M, Matsui T, Farris W, Lu A, Hyman BT, Selkoe DJ, Bertram L, Tanzi RE (2007). "Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families". J. Biol. Chem. 282 (11): 7825–32. doi:10.1074/jbc.M609168200. PMID 17244626. 
  10. ^ Duckworth WC, Bennett RG, Hamel FG (1998). "Insulin degradation: progress and potential". Endocr. Rev. 19 (5): 608–24. doi:10.1210/er.19.5.608. PMID 9793760. 
  11. ^ Lynch JA, George AM, Eisenhauer PB, Conn K, Gao W, Carreras I, Wells JM, McKee A, Ullman MD, Fine RE (2006). "Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures". J. Neurosci. Res. 83 (7): 1262–70. doi:10.1002/jnr.20809. PMID 16511862. 
  12. ^ Shen Y, Joachimiak A, Rosner MR, Tang WJ (2006). "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism". Nature 443 (7113): 870–4. doi:10.1038/nature05143. PMID 17051221. 

[edit] External links

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Proteases: metalloendopeptidases (EC 3.4.24)
ADAM proteins
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Matrix metalloproteinase
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