P28825 (MEP1A_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Meprin A subunit alpha
EC=3.4.24.18

Alternative name(s):
Endopeptidase-2
MEP-1

Gene names

Name:

Mep1a

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	747 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)

Catalytic activity	Hydrolysis of protein and peptide substrates preferentially on carboxyl side of hydrophobic residues. Ref.9 Ref.10
Cofactor	Binds 1 zinc ion per subunit By similarity.
Enzyme regulation	Inhibited by metal ion chelators EDTA and 1,10-phenanthroline, bradykinin analogs, cysteine, CONA65, and several hydroxamate compounds, particularly tyrosine hydroxamate. Not inhibited by 3,4-dichloroisocourmarin, soybean trypsin inhibitor, or the cysteine proteinase inhibitors iodoacetic acid and E-64. Ref.7 Ref.9 Ref.13
Subunit structure	Homotetramer consisting of disulfide-linked alpha subunits, homooligomer consisting of disulfide-linked alpha subunit homodimers, or heterotetramer of two alpha and two beta subunits formed by non-covalent association of two disulfide-linked heterodimers. Genetic factors determine which oligomer(s) will be formed (strain-specific). Interacts with MBL2 through its carbohydrate moiety. This interaction may inhibit its catalytic activity. Ref.8 Ref.11 Ref.12
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Kidney, intestinal brush borders and salivary ducts.
Post-translational modification	N-glycosylated; contains GlcNAc, galactose, mannose and a small amount of fucose. Ref.7 Ref.12
Sequence similarities	Belongs to the peptidase M12A family. Contains 1 EGF-like domain. Contains 1 MAM domain. Contains 1 MATH domain.
Biophysicochemical properties	Kinetic parameters: KM=29.6 µM for GRP Ref.7 Ref.9 Ref.13 KM=67.2 µM for PTH 12-34 KM=111 µM for secretin KM=30.6 µM for substance P KM=156 µM for LHRH KM=22.3 µM for alpha-MSH KM=101 µM for bradykinin KM=290 µM for Arg-Pro-Pro-Gly-Npa-Ser-Pro-Phe-Arg KM=331 µM for Arg-Pro-Pro-Gly-Npa-Ala-Pro-Phe-Arg KM=174 µM for Arg-Pro-Pro-Gly-Npa-Arg-Pro-Phe-Arg KM=226 µM for Arg-Pro-Pro-Gly-Npa-Phe-Pro-Phe-Arg KM=182 µM for Arg-Pro-Pro-Gly-Npa-Lys-Pro-Phe-Arg KM=339 µM for Arg-Pro-Pro-Gly-Npa-Glu-Pro-Phe-Arg KM=366 µM for 2ABz-Arg-Pro-Gly-Phe-Ser-Pro-Npa-Arg KM=296 µM for 2ABz-Arg-Pro-Ile-Phe-Ser-Pro-Npa-Arg KM=183 µM for 2ABz-Arg-Hyp-Gly-Phe-Ser-Pro-Npa-Arg KM=220 µM for 2ABz-Arg-Gly-Pro-Phe-Ser-Pro-Npa-Arg KM=1380 µM for 2ABz-Arg-Pro-Gly-Ala-Ser-Pro-Npa-Arg KM=1220 µM for 2ABz-Arg-Pro-Gly-Glu-Ser-Pro-Npa-Arg KM=402 µM for 2ABz-Arg-Pro-Gly-Lys-Ser-Pro-Npa-Arg KM=2460 µM for 2ABz-Arg-Pro-Gly-Leu-Ser-Pro-Npa-Arg Temperature dependence: The half-life at 58 degrees Celsius is 50 minutes.
Sequence caution	The sequence AAA75354.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened. The sequence AAH15258.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Cellular component	Membrane
Domain	EGF-like domain Signal Transmembrane Transmembrane helix
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	proteolysis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	membrane fraction Inferred from direct assay. Source: MGI
Molecular function	metalloendopeptidase activity Inferred from electronic annotation. Source: InterPro zinc ion binding 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 – 20

20

Ref.4

Propeptide

21 – 64

44

PRO_0000028879

Chain

65 – 747

683

Meprin A subunit alpha

PRO_0000028880

Regions

Topological domain

65 – 713

649

Extracellular Potential

Transmembrane

714 – 741

28

Helical; Potential

Topological domain

742 – 747

6

Cytoplasmic Potential

Domain

263 – 432

170

MAM

Domain

433 – 594

162

MATH

Domain

671 – 711

41

EGF-like

Region

65 – 262

198

Metalloprotease

Sites

Active site

155

1

By similarity

Metal binding

154

1

Zinc; catalytic By similarity

Metal binding

158

1

Zinc; catalytic By similarity

Metal binding

164

1

Zinc; catalytic By similarity

Site

601

1

Not glycosylated

Amino acid modifications

Glycosylation

28

1

N-linked (GlcNAc...) Ref.12

Glycosylation

139

1

N-linked (GlcNAc...) Ref.12

Glycosylation

221

1

N-linked (GlcNAc...) Ref.12

Glycosylation

257

1

N-linked (GlcNAc...) Ref.12

Glycosylation

317

1

N-linked (GlcNAc...) Ref.12

Glycosylation

413

1

N-linked (GlcNAc...) Ref.12

Glycosylation

439

1

N-linked (GlcNAc...) Ref.12

Glycosylation

533

1

N-linked (GlcNAc...) Ref.12

Glycosylation

540

1

N-linked (GlcNAc...) Ref.12

Disulfide bond

106 ↔ 258

By similarity

Disulfide bond

127 ↔ 146

By similarity

Disulfide bond

268 ↔ 430

By similarity

Disulfide bond

276

Interchain By similarity

Disulfide bond

307

Interchain By similarity

Disulfide bond

675 ↔ 686

By similarity

Disulfide bond

680 ↔ 695

By similarity

Disulfide bond

697 ↔ 710

By similarity

Experimental info

Mutagenesis

139

1

N → Q: Increased susceptibility to heat-inactivation. Forms homodimers and oligomers; when associated with Q-221. Inactive, impaired ability to form homodimers or oligomers; when associated with Q-257 or Q-221 and Q-257. Ref.12

Mutagenesis

141

1

S → A: Impaired ability to form homodimers or oligomers; when associated with A-259. Ref.12

Mutagenesis

221

1

N → Q: Increased susceptibility to heat-inactivation. Forms homodimers and oligomers; when associated with Q-139 or Q-257. Inactive, impaired ability to form homodimers or oligomers; when associated with Q-139 and Q-257. Ref.12

Mutagenesis

257

1

N → Q: Increased susceptibility to heat-inactivation. Forms homodimers and oligomers; when associated with Q-221. Inactive, impaired ability to form homodimers or oligomers; when associated with Q-139 or Q-139 and Q-221. Ref.12

Mutagenesis

259

1

T → A: Impaired ability to form homodimers or oligomers; when associated with A-141. Ref.12

Sequence conflict

482

1

F → L in AAA75354. Ref.1

Sequence conflict

533

1

N → I AA sequence Ref.7

Sequence conflict

540

1

N → S AA sequence Ref.7

Sequence conflict

545

1

W → T AA sequence Ref.7

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

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.

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.

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.

.

.

.

.

.

747

Helix Strand Turn

Details...

Beta strand

66 – 68

3

Helix

70 – 72

3

Beta strand

76 – 82

7

Helix

88 – 104

17

Beta strand

108 – 111

4

Beta strand

119 – 122

4

Beta strand

124 – 128

5

Beta strand

138 – 142

5

Helix

149 – 160

12

Helix

171 – 173

3

Beta strand

175 – 177

3

Helix

179 – 181

3

Helix

184 – 187

4

Helix

188 – 190

3

Beta strand

196 – 199

4

Beta strand

218 – 220

3

Turn

221 – 223

3

Beta strand

226 – 231

6

Helix

246 – 253

8

Sequences

	Sequence		Length	Mass (Da)
	P28825 [UniParc]. Last modified July 13, 2010. Version 4. Checksum: 2A1A268043559953	FASTA	747	84,231
	10 20 30 40 50 60 MLWIQPACLL SLIFSAHIAA VSIKHLLNGS DHDTDVGEQK DIFEINLAAG LNLFQGDILL 70 80 90 100 110 120 PRTRNAMRDP SSRWKLPIPY ILADNLELNA KGAILHAFEM FRLKSCVDFK PYEGESSYII 130 140 150 160 170 180 FQKLSGCWSM IGDQQVGQNI SIGEGCDFKA TIEHEILHAL GFFHEQSRTD RDDYVNIWWD 190 200 210 220 230 240 QIITDYEHNF NTYDDNTITD LNTPYDYESL MHYGPFSFNK NESIPTITTK IPEFNTIIGQ 250 260 270 280 290 300 LPDFSAIDLI RLNRMYNCTA THTLLDHCDF EKTNVCGMIQ GTRDDADWAH GDSSQPEQVD 310 320 330 340 350 360 HTLVGQCKGA GYFMFFNTSL GARGEAALLE SRILYPKRKQ QCLQFFYKMT GSPADRFEVW 370 380 390 400 410 420 VRRDDNAGKV RQLAKIQTFQ GDSDHNWKIA HVTLNEEKKF RYVFLGTKGD PGNSSGGIYL 430 440 450 460 470 480 DDITLTETPC PAGVWTIRNI SQILENTVKG DKLVSPRFYN SEGYGVGVTL YPNGRITSNS 490 500 510 520 530 540 GFLGLTFHLY SGDNDAILEW PVENRQAIMT ILDQEADTRN RMSLTLMFTT SKNQTSSAIN 550 560 570 580 590 600 GSVIWDRPSK VGVYDKDCDC FRSLDWGWGQ AISHQLLKRR NFLKGDSLII FVDFKDLTHL 610 620 630 640 650 660 NRTEVPASAR STMPRGLLLQ GQESPALGES SRKAMLEESL PSSLGQRHPS RQKRSVENTG 670 680 690 700 710 720 PMEDHNWPQY FRDPCDPNPC QNEGTCVNVK GMASCRCVSG HAFFYAGERC QAMHVHGSLL 730 740 GLLIGCIAGL IFLTFVTFST TNGKLRQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The alpha subunit of meprin A. Molecular cloning and sequencing, differential expression in inbred mouse strains, and evidence for divergent evolution of the alpha and beta subunits." Jiang W., Gorbea C.M., Flannery A.V., Beynon R.J., Grant G.A., Bond J.S. J. Biol. Chem. 267:9185-9193(1992) [PubMed: 1374387] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 65-103; 107-122; 273-292; 314-348; 370-375; 377-386; 389-398 AND 527-557. Strain: C3H/He and C57BL/6. Tissue: Kidney.
[2]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed: 19468303] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: FVB/N. Tissue: Kidney.
[4]	"Characterization of the soluble, secreted form of urinary meprin." Beynon R.J., Oliver S., Robertson D.H.L. Biochem. J. 315:461-465(1996) [PubMed: 8615815] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-25 AND 65-69.
[5]	"Correlation of the exon/intron organization to the secondary structures of the protease domain of mouse meprin alpha subunit." Jiang W., Flannery A.V. Gene 189:65-71(1997) [PubMed: 9161413] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 62-258. Strain: 129.
[6]	"The astacin family of metalloendopeptidases." Dumermuth E., Sterchi E.E., Jiang W., Wolz R.L., Bond J.S., Flannery A.V., Beynon R.J. J. Biol. Chem. 266:21381-21385(1991) [PubMed: 1939172] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 64-262.
[7]	"Meprin-A and -B. Cell surface endopeptidases of the mouse kidney." Kounnas M.Z., Wolz R.L., Gorbea C.M., Bond J.S. J. Biol. Chem. 266:17350-17357(1991) [PubMed: 1894622] [Abstract] Cited for: PROTEIN SEQUENCE OF 65-72; 315-348 AND 529-546, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, GLYCOSYLATION. Strain: ICR. Tissue: Kidney.
[8]	"Homo- and heterotetrameric forms of the membrane-bound metalloendopeptidases meprin A and B." Gorbea C.M., Flannery A.V., Bond J.S. Arch. Biochem. Biophys. 290:549-553(1991) [PubMed: 1929422] [Abstract] Cited for: SUBUNIT.
[9]	"Mapping the active site of meprin-A with peptide substrates and inhibitors." Wolz R.L., Harris R.B., Bond J.S. Biochemistry 30:8488-8493(1991) [PubMed: 1883833] [Abstract] Cited for: CATALYTIC ACTIVITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
[10]	"Marked differences between metalloproteases meprin A and B in substrate and peptide bond specificity." Bertenshaw G.P., Turk B.E., Hubbard S.J., Matters G.L., Bylander J.E., Crisman J.M., Cantley L.C., Bond J.S. J. Biol. Chem. 276:13248-13255(2001) [PubMed: 11278902] [Abstract] Cited for: CATALYTIC ACTIVITY.
[11]	"Mannan-binding protein blocks the activation of metalloproteases meprin alpha and beta." Hirano M., Ma B.Y., Kawasaki N., Okimura K., Baba M., Nakagawa T., Miwa K., Kawasaki N., Oka S., Kawasaki T. J. Immunol. 175:3177-3185(2005) [PubMed: 16116208] [Abstract] Cited for: INTERACTION WITH MBL2.
[12]	"Protease domain glycans affect oligomerization, disulfide bond formation, and stability of the meprin A metalloprotease homo-oligomer." Ishmael S.S., Ishmael F.T., Jones A.D., Bond J.S. J. Biol. Chem. 281:37404-37415(2006) [PubMed: 17040911] [Abstract] Cited for: SUBUNIT, GLYCOSYLATION AT ASN-28; ASN-139; ASN-221; ASN-257; ASN-317; ASN-413; ASN-439; ASN-533 AND ASN-540, MUTAGENESIS OF ASN-139; SER-141; ASN-221; ASN-257 AND THR-259.
[13]	"Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities." Bylander J.E., Bertenshaw G.P., Matters G.L., Hubbard S.J., Bond J.S. Biol. Chem. 388:1163-1172(2007) [PubMed: 17976009] [Abstract] Cited for: ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
[14]	"Implications of the three-dimensional structure of astacin for the structure and function of the astacin family of zinc-endopeptidases." Stoecker W., Gomis-Rueth F.-X., Bode W., Zwilling R. Eur. J. Biochem. 214:215-231(1993) [PubMed: 8508794] [Abstract] Cited for: 3D-STRUCTURE MODELING.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M74897 mRNA. Translation: AAA75354.1. Different initiation.
CT010585 Genomic DNA. Translation: CAQ11110.1.
BC015258 mRNA. Translation: AAH15258.1. Different initiation.
U62765 Genomic DNA. Translation: AAC53194.1.

IPI

IPI00314042.

PIR

A40195.

RefSeq

NP_032611.2. NM_008585.2.

UniGene

Mm.5346.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IAF	model	-	A	65-261	[»]

ProteinModelPortal

P28825.

SMR

P28825. Positions 66-260, 429-600, 666-712.

ModBase

Search...

Protein-protein interaction databases

STRING

P28825.

Protein family/group databases

MEROPS

M12.002.

Proteomic databases

PRIDE

P28825.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000024707; ENSMUSP00000024707; ENSMUSG00000023914.
ENSMUST00000117137; ENSMUSP00000113838; ENSMUSG00000023914.

GeneID

17287.

KEGG

mmu:17287.

UCSC

uc008cpc.1. mouse.

Organism-specific databases

CTD

4224.

MGI

MGI:96963. Mep1a.

Phylogenomic databases

eggNOG

roNOG14928.

HOVERGEN

HBG052457.

InParanoid

P28825.

OrthoDB

EOG4S4PFJ.

Gene expression databases

ArrayExpress

P28825.

Bgee

P28825.

CleanEx

MM_MEP1A.

Genevestigator

P28825.

GermOnline

ENSMUSG00000023914. Mus musculus.

Family and domain databases

InterPro

IPR008985. ConA-like_lec_gl.
IPR006209. EGF.
IPR006210. EGF-like.
IPR000742. EGF_3.
IPR000998. MAM_dom.
IPR002083. MATH.
IPR024079. MetalloPept_cat_dom.
IPR008294. Pept_M12A_Meprin.
IPR001506. Peptidase_M12A.
IPR006026. Peptidase_Metallo.
IPR008974. TRAF-like.
IPR013322. TRAF-type.
[Graphical view]

Gene3D

G3DSA:3.40.390.10. G3DSA:3.40.390.10. 1 hit.
G3DSA:2.60.210.10. TRAF-type. 1 hit.

KO

K01395.

Pfam

PF01400. Astacin. 1 hit.
PF00008. EGF. 1 hit.
PF00629. MAM. 1 hit.
PF00917. MATH. 1 hit.
[Graphical view]

PIRSF

PIRSF001196. Meprin. 1 hit.

PRINTS

PR00480. ASTACIN.
PR00020. MAMDOMAIN.

SMART

SM00181. EGF. 1 hit.
SM00137. MAM. 1 hit.
SM00061. MATH. 1 hit.
SM00235. ZnMc. 1 hit.
[Graphical view]

SUPFAM

SSF49899. ConA_like_lec_gl. 1 hit.
SSF49599. Traf_like. 1 hit.

PROSITE

PS00022. EGF_1. False negative.
PS01186. EGF_2. False negative.
PS50026. EGF_3. 1 hit.
PS00740. MAM_1. 1 hit.
PS50060. MAM_2. 1 hit.
PS50144. MATH. 1 hit.
PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

SOURCE

Search...

Entry information

Entry name

MEP1A_MOUSE

Accession

Primary (citable) accession number: P28825
Secondary accession number(s): B0V2P9, Q91WH9

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 1992
Last sequence update:	July 13, 2010
Last modified:	November 16, 2011
This is version 118 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program