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P35559 (IDE_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified May 14, 2014. Version 118. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Insulin-degrading enzyme

EC=3.4.24.56
Alternative name(s):
Insulin protease
Short name=Insulinase
Insulysin
Gene names
Name:Ide
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length1019 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Plays a role in the cellular breakdown of insulin, IAPP, glucagon, bradykinin, kallidin and other peptides, and thereby plays a role in intercellular peptide signaling. Degrades amyloid formed by APP and IAPP.

Catalytic activity

Degradation of insulin, glucagon and other polypeptides. No action on proteins.

Cofactor

Binds 1 zinc ion per subunit. Ref.5

Enzyme regulation

Activated by ATP, other nucleotide triphosphates and small peptides. Inhibited by bacitracin By similarity. Ref.5

Subunit structure

Homodimer. Can form higher oligomers. Ref.5

Subcellular location

Cytoplasm. Cell membrane By similarity. Secreted By similarity.

Domain

The SlyX motif may be involved in the non-conventional secretion of the protein By similarity.

Miscellaneous

ATP-binding induces a conformation change By similarity.

Sequence similarities

Belongs to the peptidase M16 family.

Ontologies

Keywords
   Cellular componentCell membrane
Cytoplasm
Membrane
Secreted
   LigandATP-binding
Metal-binding
Nucleotide-binding
Zinc
   Molecular functionHydrolase
Metalloprotease
Protease
   Technical term3D-structure
Allosteric enzyme
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processATP catabolic process

Inferred from direct assay PubMed 17259336. Source: GOC

beta-amyloid metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

bradykinin catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

cellular protein catabolic process

Inferred from direct assay PubMed 11235899. Source: RGD

determination of adult lifespan

Inferred from electronic annotation. Source: Ensembl

hormone catabolic process

Inferred from direct assay PubMed 15494400. Source: RGD

insulin catabolic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of proteolysis

Inferred from direct assay PubMed 9000694. Source: RGD

peptide catabolic process

Traceable author statement PubMed 11809755. Source: RGD

positive regulation of protein oligomerization

Inferred from electronic annotation. Source: Ensembl

protein heterooligomerization

Inferred from direct assay PubMed 9000694. Source: RGD

protein homotetramerization

Inferred from direct assay PubMed 15494400. Source: RGD

proteolysis involved in cellular protein catabolic process

Inferred from mutant phenotype PubMed 15749695. Source: RGD

ubiquitin homeostasis

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcell surface

Inferred from direct assay PubMed 10684867. Source: RGD

cytosol

Inferred from direct assay PubMed 15985623. Source: RGD

cytosolic proteasome complex

Inferred from direct assay PubMed 9000694. Source: RGD

extracellular space

Inferred from direct assay PubMed 10684867. Source: RGD

mitochondrion

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from direct assay PubMed 15985623. Source: RGD

peroxisomal matrix

Inferred from direct assay PubMed 11235899. Source: RGD

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from sequence or structural similarity. Source: UniProtKB

ATPase activity

Inferred from direct assay PubMed 17259336. Source: RGD

beta-amyloid binding

Inferred from physical interaction PubMed 18411275. Source: RGD

beta-endorphin binding

Inferred from mutant phenotype PubMed 15749695. Source: RGD

insulin binding

Inferred from mutant phenotype PubMed 15749695. Source: RGD

metalloendopeptidase activity

Inferred from sequence or structural similarity. Source: UniProtKB

peptidase activity

Traceable author statement PubMed 11809755. Source: RGD

peptide hormone binding

Inferred from physical interaction PubMed 15494400. Source: RGD

protein homodimerization activity

Inferred from direct assay PubMed 15494400. Source: RGD

zinc ion binding

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 10191019Insulin-degrading enzyme
PRO_0000074406

Regions

Nucleotide binding895 – 9017ATP
Motif853 – 8586SlyX motif

Sites

Active site1111Proton acceptor By similarity
Metal binding1081Zinc
Metal binding1121Zinc
Metal binding1891Zinc
Binding site4291ATP

Amino acid modifications

Modified residue1921N6-succinyllysine By similarity
Modified residue6971N6-succinyllysine By similarity

Experimental info

Mutagenesis4291R → S: Greatly decreased activation by polyphosphate anions. Ref.6
Mutagenesis8981K → A: Greatly decreased activation by polyphosphate anions, and deficient in activation by small peptides; when associated with A-899 and A-901. Ref.6
Mutagenesis8991K → A: Greatly decreased activation by polyphosphate anions, and deficient in activation by small peptides; when associated with A-898 and A-901. Ref.6
Mutagenesis9011S → A: Greatly decreased activation by polyphosphate anions, and deficient in activation by small peptides; when associated with A-898 and A-899. Ref.6

Secondary structure

................................................................................................................................................... 1019
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P35559 [UniParc].

Last modified June 1, 1994. Version 1.
Checksum: 9DB297A7F1877CEC

FASTA1,019117,710
        10         20         30         40         50         60 
MRNGLVWLLH PALPSTLHSI LGARPPPVKR LCGFPKQIYS TMNNPAIQRI EDHIVKSPED 

        70         80         90        100        110        120 
KREYRGLELA NGIKVLLISD PTTDKSSAAL DVHIGSLSDP PNIPGLSHFC EHMLFLGTKK 

       130        140        150        160        170        180 
YPKENEYSQF LSEHAGSSNA FTSGEHTNYY FDVSHEHLEG ALDRFAQFFL CPLFDASCKD 

       190        200        210        220        230        240 
REVNAVDSEH EKNVMNDAWR LFQLEKATGN PKHPFSKFGT GNKYTLETRP NQEGIDVREE 

       250        260        270        280        290        300 
LLKFHSTYYS SNLMAICVLG RESLDDLTNL VVKLFSEVEN KNVPLPEFPE HPFQEEHLKQ 

       310        320        330        340        350        360 
LYKIVPIKDI RNLYVTFPIP DLQQYYKSNP GHYLGHLIGH EGPGSLLSEL KSKGWVNTLV 

       370        380        390        400        410        420 
GGQKEGARGF MFFIINVDLT EEGLLHVEDI ILHMFQYIQK LRAEGPQEWV FQECKDLNAV 

       430        440        450        460        470        480 
AFRFKDKERP RGYTSKIAGK LHYYPLNGVL TAEYLLEEFR PDLIDMVLDK LRPENVRVAI 

       490        500        510        520        530        540 
VSKSFEGKTD RTEQWYGTQY KQEAIPEDVI QKWQNADLNG KFKLPTKNEF IPTNFEILAL 

       550        560        570        580        590        600 
EKDATPYPAL IKDTAMSKLW FKQDDKFFLP KACLNFEFFS PFAYVDPLHC NMAYLYLELL 

       610        620        630        640        650        660 
KDSLNEYAYA AELAGLSYDL QNTIYGMYLS VKGYNDKQPI LLKKITEKMA TFEIDKKRFE 

       670        680        690        700        710        720 
IIKEAYMRSL NNFRAEQPHQ HAMYYLRLLM TEVAWTKDEL KEALDDVTLP RLKAFIPQLL 

       730        740        750        760        770        780 
SRLHIEALLH GNITKQAALG VMQMVEDTLI EHAHTKPLLP SQLVRYREVQ LPDRGWFVYQ 

       790        800        810        820        830        840 
RRNEVHNNCG IEIYYQTDMQ STSENMFLEL FCQIISEPCF NTLRTKEQLG YIVFSGPRRA 

       850        860        870        880        890        900 
NGIQGLRFII QSEKPPHYLE SRVEAFLITM EKAIEDMTEE AFQKHIQALA IRRLDKPKKL 

       910        920        930        940        950        960 
SAECAKYWGE IISQQYNYDR DNIEVAYLKT LSKDDIIKFY KEMLAVDAPR RHKVSVHVLA 

       970        980        990       1000       1010 
REMDSCPVVG EFPSQNDINL SEAPPLPQPE VIHNMTEFKR GLPLFPLVKP HINFMAAKL 

« Hide

References

[1]"The rat insulin-degrading enzyme. Molecular cloning and characterization of tissue-specific transcripts."
Baumeister H., Mueller D., Rehbein M., Richter D.
FEBS Lett. 317:250-254(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: Wistar.
Tissue: Brain.
[2]"Insulin-degrading enzyme is differentially expressed and developmentally regulated in various rat tissues."
Kuo W.L., Montag A.G., Rosner M.R.
Endocrinology 132:604-611(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 898-995.
Strain: Sprague-Dawley.
[3]"Atrial natriuretic peptide (ANP) is a high-affinity substrate for rat insulin-degrading enzyme."
Mueller D., Baumeister H., Buck F., Richter D.
Eur. J. Biochem. 202:285-292(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: PARTIAL PROTEIN SEQUENCE, ACTIVITY ON ANP.
[4]"Rat insulin-degrading enzyme: cleavage pattern of the natriuretic peptide hormones ANP, BNP, and CNP revealed by HPLC and mass spectrometry."
Mueller D., Schulze C., Baumeister H., Buck F., Richter D.
Biochemistry 31:11138-11143(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: ACTIVITY ON ANP; BNP AND CNP.
[5]"Identification of the allosteric regulatory site of insulysin."
Noinaj N., Bhasin S.K., Song E.S., Scoggin K.E., Juliano M.A., Juliano L., Hersh L.B., Rodgers D.W.
PLoS ONE 6:E20864-E20864(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) OF 42-1019 OF WILD TYPE AND MUTANT PHE-111, SUBUNIT, COFACTOR, ZINC-BINDING SITES, ENZYME REGULATION, ALLOSTERIC REGULATION.
[6]"Anion activation site of insulin-degrading enzyme."
Noinaj N., Song E.S., Bhasin S., Alper B.J., Schmidt W.K., Hersh L.B., Rodgers D.W.
J. Biol. Chem. 287:48-57(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS), ATP-BINDING SITE, MUTAGENESIS OF ARG-429; LYS-898; LYS-899 AND SER-901.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X67269 mRNA. Translation: CAA47689.1.
S53721 mRNA. Translation: AAB25205.1.
PIRS29509.
RefSeqNP_037291.1. NM_013159.1.
UniGeneRn.202992.
Rn.45029.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3P7LX-ray2.08A42-1019[»]
3P7OX-ray2.14A1-1019[»]
3TUVX-ray2.27A1-1019[»]
ProteinModelPortalP35559.
SMRP35559. Positions 43-1016.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid247729. 1 interaction.
STRING10116.ENSRNOP00000023342.

Protein family/group databases

MEROPSM16.002.

PTM databases

PhosphoSiteP35559.

Proteomic databases

PaxDbP35559.
PRIDEP35559.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000023342; ENSRNOP00000023342; ENSRNOG00000016833.
GeneID25700.
KEGGrno:25700.
UCSCRGD:2861. rat.

Organism-specific databases

CTD3416.
RGD2861. Ide.

Phylogenomic databases

eggNOGCOG1025.
GeneTreeENSGT00530000063327.
HOGENOMHOG000161331.
HOVERGENHBG106799.
InParanoidP35559.
KOK01408.
OMASIFHIIK.
OrthoDBEOG7HHWRD.
PhylomeDBP35559.
TreeFamTF106275.

Enzyme and pathway databases

SABIO-RKP35559.

Gene expression databases

GenevestigatorP35559.

Family and domain databases

Gene3D3.30.830.10. 4 hits.
InterProIPR011249. Metalloenz_LuxS/M16.
IPR011237. Pept_M16_dom.
IPR011765. Pept_M16_N.
IPR001431. Pept_M16_Zn_BS.
IPR007863. Peptidase_M16_C.
[Graphical view]
PfamPF00675. Peptidase_M16. 1 hit.
PF05193. Peptidase_M16_C. 2 hits.
[Graphical view]
SUPFAMSSF63411. SSF63411. 4 hits.
PROSITEPS00143. INSULINASE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP35559.
NextBio607727.
PROP35559.

Entry information

Entry nameIDE_RAT
AccessionPrimary (citable) accession number: P35559
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: May 14, 2014
This is version 118 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references