Insulin-degrading enzyme - Rattus norvegicus (Rat)

Preferred order of sections

Names and origin

Protein names

Recommended name:
Insulin-degrading enzyme
EC=3.4.24.56

Alternative name(s):
Insulin protease
Short name=Insulinase
Insulysin

Gene names

Name:

Ide

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	1019 AA.
Sequence status	Complete.
Protein existence	Evidence 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 component	Cell membrane Cytoplasm Membrane Secreted
Ligand	ATP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
Technical term	3D-structure Allosteric enzyme Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	beta-amyloid metabolic process Inferred from sequence or structural similarity. Source: UniProtKB bradykinin catabolic process Inferred from sequence or structural similarity. Source: UniProtKB determination of adult lifespan Inferred from electronic annotation. Source: Compara hormone catabolic process Inferred from direct assay PubMed 15494400. Source: RGD insulin catabolic process Inferred from electronic annotation. Source: Compara negative regulation of proteolysis Inferred from direct assay PubMed 9000694. Source: RGD positive regulation of protein oligomerization Inferred from electronic annotation. Source: Compara 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: Compara
Cellular_component	cell surface Inferred from direct assay PubMed 10684867. 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: Compara 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_function	ATP 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 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1019

1019

Insulin-degrading enzyme

PRO_0000074406

Regions

Nucleotide binding

895 – 901

7

ATP

Motif

853 – 858

6

SlyX motif

Sites

Active site

111

1

Proton acceptor By similarity

Metal binding

108

1

Zinc

Metal binding

112

1

Zinc

Metal binding

189

1

Zinc

Binding site

429

1

ATP

Experimental info

Mutagenesis

429

1

R → S: Greatly decreased activation by polyphosphate anions. Ref.6

Mutagenesis

898

1

K → A: Greatly decreased activation by polyphosphate anions, and deficient in activation by small peptides; when associated with A-899 and A-901. Ref.6

Mutagenesis

899

1

K → A: Greatly decreased activation by polyphosphate anions, and deficient in activation by small peptides; when associated with A-898 and A-901. Ref.6

Mutagenesis

901

1

S → 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

1

.

1019

Helix Strand Turn

Details...

Sequences

Sequence

Length

Mass (Da)

Tools

P35559 [UniParc].

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

FASTA

1,019

117,710

        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

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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.

IPI

IPI00199609.

PIR

S29509.

RefSeq

NP_037291.1. NM_013159.1.

UniGene

Rn.45029.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3P7L	X-ray	2.08	A	42-1019	[»]
3P7O	X-ray	2.14	A	1-1019	[»]
3TUV	X-ray	2.27	A	1-1019	[»]

ProteinModelPortal

P35559.

SMR

P35559. Positions 43-1016.

ModBase

Search...

Protein-protein interaction databases

STRING

10116.ENSRNOP00000023342.

Protein family/group databases

MEROPS

M16.002.

PTM databases

PhosphoSite

P35559.

Proteomic databases

PaxDb

P35559.

PRIDE

P35559.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSRNOT00000023342; ENSRNOP00000023342; ENSRNOG00000016833.

GeneID

25700.

KEGG

rno:25700.

UCSC

RGD:2861. rat.

Organism-specific databases

CTD

3416.

RGD

2861. Ide.

Phylogenomic databases

eggNOG

COG1025.

GeneTree

ENSGT00530000063327.

HOGENOM

HOG000161331.

HOVERGEN

HBG106799.

InParanoid

P35559.

KO

K01408.

OMA

FFHELRT.

OrthoDB

EOG4H4630.

Enzyme and pathway databases

SABIO-RK

P35559.

Gene expression databases

ArrayExpress

P35559.

Genevestigator

P35559.

GermOnline

ENSRNOG00000016833. Rattus norvegicus.

Family and domain databases

Gene3D

3.30.830.10. 4 hits.

InterPro

IPR011249. Metalloenz_LuxS/M16.
IPR011237. Pept_M16_dom.
IPR011765. Pept_M16_N.
IPR001431. Pept_M16_Zn_BS.
IPR007863. Peptidase_M16_C.
[Graphical view]

Pfam

PF00675. Peptidase_M16. 1 hit.
PF05193. Peptidase_M16_C. 2 hits.
[Graphical view]

SUPFAM

SSF63411. Metalloenz_metal-bd. 4 hits.

PROSITE

PS00143. INSULINASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P35559.

NextBio

607727.

Entry information

Entry name

IDE_RAT

Accession

Primary (citable) accession number: P35559

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	April 3, 2013
This is version 109 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Relevant documents

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families