P26349 (EXE4_HELSU) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names	Recommended name: Exendin-4 Alternative name(s): INN=Exenatide
Organism	Heloderma suspectum (Gila monster)
Taxonomic identifier	8554 [NCBI]
Taxonomic lineage	Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Lepidosauria › Squamata › Scleroglossa › Anguimorpha › Helodermatidae › Heloderma

Protein attributes

Sequence length	87 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Venom protein that mimics the incretin hormone glucagon-like peptide 1 (GLP-1). It stimulates insulin synthesis and secretion, protects against beta-cell apoptosis in response to different insults, and promotes beta-cell proliferation. It also promotes satiety, reduces food intake, reduces fat deposition, reduces body weight and inhibits gastric emptying. Interacts with GLP-1 receptor (GLP1R). Induces hypotension that is mediated by relaxation of cardiac smooth muscle. Ref.5 Ref.6
Subcellular location	Secreted.
Tissue specificity	Expressed by the venom gland or the salivary gland (still contreversial). Ref.2
Pharmaceutical use	Available under the name Byetta (Amylin/Eli Lilly). Used for the treatment of type 2 diabetes. Enhances insulin secretion in response to elevated plasma glucose levels.
Sequence similarities	Belongs to the glucagon family.
Mass spectrometry	Molecular mass is 4186.02 Da from positions 48 - 86. Determined by MALDI. Ref.3

Ontologies

Keywords
Cellular component	Secreted
Domain	Signal
Molecular function	Hypotensive agent Toxin
PTM	Amidation Cleavage on pair of basic residues
Technical term	3D-structure Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Cellular component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	hormone activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

23

Potential

Propeptide

24 – 45

22

PRO_0000011421

Peptide

48 – 86

39

Exendin-4 Ref.3 Ref.4

PRO_0000011422

Amino acid modifications

Modified residue

86

1

Serine amide

Experimental info

Sequence conflict

13

1

F → G no nucleotide entry Ref.2

Secondary structure

1

.

.

.

.

.

.

87

Helix Strand Turn

Details...

Helix

54 – 74

21

Helix

77 – 79

3

Beta strand

80 – 82

3

Sequences

	Sequence		Length	Mass (Da)
	P26349 [UniParc]. Last modified July 15, 1998. Version 2. Checksum: 656BA6E3D87454A2	FASTA	87	9,479
	10 20 30 40 50 60 MKIILWLCVF GLFLATLFPI SWQMPVESGL SSEDSASSES FASKIKRHGE GTFTSDLSKQ 70 80 MEEEAVRLFI EWLKNGGPSS GAPPPSG

References

[1]	"Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard." Chen Y.E., Drucker D.J. J. Biol. Chem. 272:4108-4115(1997) [PubMed: 9020121] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Salivary gland.
[2]	"Molecular cloning of the helodermin and exendin-4 cDNAs in the lizard. Relationship to vasoactive intestinal polypeptide/pituitary adenylate cyclase activating polypeptide and glucagon-like peptide 1 and evidence against the existence of mammalian homologues." Pohl M., Wank S.A. J. Biol. Chem. 273:9778-9784(1998) [PubMed: 9545315] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY. Tissue: Salivary gland.
[3]	"Isolation and cloning of exendin precursor cDNAs from single samples of venom from the Mexican beaded lizard (Heloderma horridum) and the Gila monster (Heloderma suspectum)." Chen T., Kwok H., Ivanyi C., Shaw C. Toxicon 47:288-295(2006) [PubMed: 16386282] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 48-86, MASS SPECTROMETRY. Tissue: Venom.
[4]	"Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas." Eng J., Kleinman W.A., Singh L., Singh G., Raufman J.-P. J. Biol. Chem. 267:7402-7405(1992) [PubMed: 1313797] [Abstract] Cited for: PROTEIN SEQUENCE OF 48-86. Tissue: Venom.
[5]	"Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor." Thorens B., Porret A., Buehler L., Deng S., Morel P., Widmann C. Diabetes 42:1678-1682(1993) [PubMed: 8405712] [Abstract] Cited for: FUNCTION.
[6]	"Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma)." Fry B.G., Roelants K., Winter K., Hodgson W.C., Griesman L., Kwok H.F., Scanlon D., Karas J., Shaw C., Wong L., Norman J.A. Mol. Biol. Evol. 27:395-407(2010) [PubMed: 19837656] [Abstract] Cited for: SYNTHESIS OF 48-86, FUNCTION.
[7]	"The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent." Furman B.L. Toxicon 0:0-0(2011) [PubMed: 21194543] [Abstract] Cited for: REVIEW, PHARMACEUTICAL.
[8]	"Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states." Neidigh J.W., Fesinmeyer R.M., Prickett K.S., Andersen N.H. Biochemistry 40:13188-13200(2001) [PubMed: 11683627] [Abstract] Cited for: STRUCTURE BY NMR OF 48-86.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U77613 mRNA. Translation: AAB51130.1.

PIR

HWGH4G. A42486.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1JRJ	NMR	-	A	48-86	[»]
3C59	X-ray	2.30	B	56-86	[»]
3C5T	X-ray	2.10	B	56-86	[»]

ProteinModelPortal

P26349.

SMR

P26349. Positions 48-86.

ModBase

Search...

Protocols and materials databases

StructuralBiologyKnowledgebase

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Phylogenomic databases

HOVERGEN

HBG081487.

Family and domain databases

InterPro

IPR000532. Glucagon_GIP_secretin_VIP.
[Graphical view]

Pfam

PF00123. Hormone_2. 1 hit.
[Graphical view]

SMART

SM00070. GLUCA. 1 hit.
[Graphical view]

PROSITE

PS00260. GLUCAGON. 1 hit.
[Graphical view]

ProtoNet

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Entry information

Entry name

EXE4_HELSU

Accession

Primary (citable) accession number: P26349

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1992
Last sequence update:	July 15, 1998
Last modified:	January 25, 2012
This is version 62 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Animal Toxin Annotation Program

Annotation program

Chordata Protein Annotation Program