Q16820 (MEP1B_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Meprin A subunit beta
EC=3.4.24.63

Alternative name(s):
Endopeptidase-2
Meprin B
N-benzoyl-L-tyrosyl-P-amino-benzoic acid hydrolase subunit beta
PABA peptide hydrolase
PPH beta

Gene names

Name:

MEP1B

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	701 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	Membrane metallopeptidase that sheds many membrane-bound proteins. Known substrates include: FGF19, VGFA, IL1B, IL18, procollagen I and III, E-cadherin, KLK7, gastrin, ADAM10, tenascin-C. The presence of several pro-inflammatory cytokine among substrates implicate MEP1B in inflammation. It is also involved in tissue remodeling due to its capability to degrade extracellular matrix components. Ref.12
Catalytic activity	Hydrolysis of proteins, including azocasein, and peptides. Hydrolysis of 5-His-|-Leu-6, 6-Leu-|-Cys-7, 14-Ala-|-Leu-15 and 19-Cys-|-Gly-20 bonds in insulin B chain. Exhibits a strong preference for acidic amino-acids at the P1' position. Ref.12
Cofactor	Binds 1 zinc ion per subunit. Ref.14
Enzyme regulation	Strongly inhibited by fetuin-A/AHSG. Ref.10 Ref.13
Subunit structure	Homotetramer consisting of disulfide-linked beta subunits, or heterotetramer of two alpha and two beta subunits formed by non-covalent association of two disulfide-linked heterodimers By similarity. Interacts with MBL2 through its carbohydrate moiety. This interaction may inhibit its catalytic activity By similarity. Ref.14
Subcellular location	Cell membrane; Single-pass type I membrane protein. Secreted. Note: Homodimers are essentially membrane bound but may also be shed from the surface by ADAM-10 and ADAM-17. Ref.5 Ref.14
Tissue specificity	The major site of expression is the brush border membrane of small intestinal and kidney epithelial cells. Ref.6
Post-translational modification	N-glycosylated; contains high mannose and/or complex biantennary structures. Ref.6 Ref.14 O-glycosylation protect the C-terminal region from proteolytic cleavage and diminish secretion, this seems to be specific to human. Proteolytically activated by trypsin in the intestinal lumen and kallikrein-related peptidases in other tissues.
Sequence similarities	Belongs to the peptidase M12A family. Contains 1 EGF-like domain. Contains 1 MAM domain. Contains 1 MATH domain.

Ontologies

Keywords
Biological process	Inflammatory response
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Polymorphism
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	digestion Traceable author statement Ref.1. Source: ProtInc inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW proteolysis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	extracellular space Traceable author statement Ref.1. Source: ProtInc integral to plasma membrane Traceable author statement Ref.1. Source: ProtInc
Molecular_function	metalloendopeptidase activity Inferred from electronic annotation. Source: Compara zinc ion binding Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Potential

Propeptide

23 – 61

39

PRO_0000028883

Chain

62 – 701

640

Meprin A subunit beta

PRO_0000028884

Regions

Topological domain

23 – 652

630

Extracellular Potential

Transmembrane

653 – 673

21

Helical; Potential

Topological domain

674 – 701

28

Cytoplasmic Potential

Domain

260 – 429

170

MAM

Domain

430 – 585

156

MATH

Domain

604 – 644

41

EGF-like

Region

64 – 259

196

Metalloprotease

Region

595 – 607

13

Required for proteolytic processing

Sites

Active site

153

1

By similarity

Metal binding

52

1

Zinc; catalytic

Metal binding

152

1

Zinc; catalytic

Metal binding

156

1

Zinc; catalytic

Metal binding

162

1

Zinc; catalytic

Site

238

1

Mediates preference for acidic residues at subsite P1'

Amino acid modifications

Glycosylation

218

1

N-linked (GlcNAc...) Ref.14

Glycosylation

254

1

N-linked (GlcNAc...) Ref.14

Glycosylation

370

1

N-linked (GlcNAc...) Ref.14

Glycosylation

421

1

N-linked (GlcNAc...) Potential

Glycosylation

436

1

N-linked (GlcNAc...) Ref.14

Glycosylation

445

1

N-linked (GlcNAc...) Ref.14

Glycosylation

547

1

N-linked (GlcNAc...) Ref.14

Glycosylation

592

1

N-linked (GlcNAc...) Ref.14

Glycosylation

593

1

O-linked (GalNAc...) Potential

Glycosylation

594

1

O-linked (GalNAc...) Potential

Glycosylation

599

1

O-linked (GalNAc...) Potential

Glycosylation

603

1

O-linked (GalNAc...) Potential

Disulfide bond

103 ↔ 255

Ref.14

Disulfide bond

124 ↔ 144

Ref.14

Disulfide bond

265 ↔ 427

Ref.14

Disulfide bond

273

Interchain By similarity

Disulfide bond

305

Interchain Ref.14

Disulfide bond

492

Interchain By similarity

Disulfide bond

608 ↔ 619

By similarity

Disulfide bond

613 ↔ 628

By similarity

Disulfide bond

630 ↔ 643

By similarity

Natural variations

Natural variant

326

1

V → M.
Corresponds to variant rs9959396 [ dbSNP | Ensembl ].

VAR_057064

Natural variant

695

1

P → L. Ref.1 Ref.3
Corresponds to variant rs616114 [ dbSNP | Ensembl ].

VAR_057065

Experimental info

Mutagenesis

248

1

K → Y: Decreased activity toward gastrin. Ref.7

Mutagenesis

595 – 607

13

Missing: Abolishes secretion. Ref.6

Sequence conflict

71

1

W → S AA sequence Ref.4

Sequence conflict

74

1

T → P AA sequence Ref.4

Sequence conflict

546

1

S → P in AAU05377. Ref.2

Sequence conflict

546

1

S → P in AAI36560. Ref.3

Sequence conflict

546

1

S → P in AAI44245. Ref.3

Sequence conflict

698

1

Missing in CAA57107. Ref.1

Secondary structure

1

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701

Helix Strand Turn

Details...

Turn

29 – 32

4

Helix

37 – 43

7

Turn

50 – 52

3

Beta strand

63 – 65

3

Helix

67 – 69

3

Beta strand

73 – 79

7

Helix

85 – 101

17

Beta strand

105 – 108

4

Beta strand

113 – 119

7

Beta strand

122 – 126

5

Beta strand

133 – 140

8

Helix

147 – 158

12

Helix

163 – 165

3

Helix

169 – 171

3

Beta strand

173 – 175

3

Helix

177 – 179

3

Helix

185 – 188

4

Turn

193 – 195

3

Turn

213 – 216

4

Beta strand

217 – 221

5

Beta strand

223 – 228

6

Helix

229 – 231

3

Turn

232 – 236

5

Helix

243 – 252

10

Beta strand

259 – 265

7

Helix

272 – 274

3

Beta strand

276 – 278

3

Beta strand

280 – 282

3

Beta strand

285 – 289

5

Beta strand

292 – 294

3

Beta strand

299 – 304

6

Beta strand

311 – 315

5

Beta strand

317 – 319

3

Beta strand

324 – 328

5

Beta strand

335 – 337

3

Beta strand

339 – 347

9

Beta strand

354 – 363

10

Beta strand

366 – 379

14

Beta strand

382 – 384

3

Beta strand

386 – 392

7

Beta strand

398 – 405

8

Beta strand

412 – 425

14

Beta strand

429 – 434

6

Helix

438 – 440

3

Beta strand

447 – 449

3

Beta strand

460 – 466

7

Beta strand

469 – 480

12

Helix

485 – 487

3

Beta strand

494 – 501

8

Helix

508 – 510

3

Beta strand

514 – 519

6

Beta strand

527 – 531

5

Helix

536 – 539

4

Beta strand

541 – 544

4

Beta strand

550 – 564

15

Helix

565 – 568

4

Beta strand

573 – 575

3

Beta strand

578 – 587

10

Helix

589 – 591

3

Sequences

	Sequence		Length	Mass (Da)
	Q16820 [UniParc]. Last modified May 18, 2010. Version 3. Checksum: 4733DBF018A4F3CD	FASTA	701	79,571
	10 20 30 40 50 60 MDLWNLSWFL FLDALLVISG LATPENFDVD GGMDQDIFDI NEGLGLDLFE GDIRLDRAQI 70 80 90 100 110 120 RNSIIGEKYR WPHTIPYVLE DSLEMNAKGV ILNAFERYRL KTCIDFKPWA GETNYISVFK 130 140 150 160 170 180 GSGCWSSVGN RRVGKQELSI GANCDRIATV QHEFLHALGF WHEQSRSDRD DYVRIMWDRI 190 200 210 220 230 240 LSGREHNFNT YSDDISDSLN VPYDYTSVMH YSKTAFQNGT EPTIVTRISD FEDVIGQRMD 250 260 270 280 290 300 FSDSDLLKLN QLYNCSSSLS FMDSCSFELE NVCGMIQSSG DNADWQRVSQ VPRGPESDHS 310 320 330 340 350 360 NMGQCQGSGF FMHFDSSSVN VGATAVLESR TLYPKRGFQC LQFYLYNSGS ESDQLNIYIR 370 380 390 400 410 420 EYSADNVDGN LTLVEEIKEI PTGSWQLYHV TLKVTKKFRV VFEGRKGSGA SLGGLSIDDI 430 440 450 460 470 480 NLSETRCPHH IWHIRNFTQF IGSPNGTLYS PPFYSSKGYA FQIYLNLAHV TNAGIYFHLI 490 500 510 520 530 540 SGANDDQLQW PCPWQQATMT LLDQNPDIRQ RMSNQRSITT DPFMTTDNGN YFWDRPSKVG 550 560 570 580 590 600 TVALFSNGTQ FRRGGGYGTS AFITHERLKS RDFIKGDDVY ILLTVEDISH LNSTQIQLTP 610 620 630 640 650 660 APSVQDLCSK TTCKNDGVCT VRDGKAECRC QSGEDWWYMG ERCEKRGSTR DTIVIAVSST 670 680 690 700 VAVFALMLII TLVSVYCTRK KYRERMSSNR PNLTPQNQHA F

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Polarised expression of human intestinal N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase (human meprin) alpha and beta subunits in Madin-Darby canine kidney cells." Eldering J.A., Gruenberg J., Hahn D., Croes H.J., Fransen J.A., Sterchi E.E. Eur. J. Biochem. 247:920-932(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 62-105, VARIANT LEU-695. Tissue: Intestine.
[2]	"Expression of human meprin beta." Haun R.S. Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Small intestine.
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT LEU-695. Tissue: Testis.
[4]	"Cloning of the PABA peptide hydrolase alpha subunit (PPH alpha) from human small intestine and its expression in COS-1 cells." Dumermuth E., Eldering J.A., Gruenberg J., Jiang W., Sterchi E.E. FEBS Lett. 335:367-375(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 62-79. Tissue: Small intestine mucosa.
[5]	"N-Benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase beta (human meprinbeta). A 13-amino-acid sequence is required for proteolytic processing and subsequent secretion." Pischitzis A., Hahn D., Leuenberger B., Sterchi E.E. Eur. J. Biochem. 261:421-429(1999) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING.
[6]	"Human meprin beta: O-linked glycans in the intervening region of the type I membrane protein protect the C-terminal region from proteolytic cleavage and diminish its secretion." Leuenberger B., Hahn D., Pischitzis A., Hansen M.K., Sterchi E.E. Biochem. J. 369:659-665(2003) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT SER-593; THR-594; THR-599 AND SER-603, TISSUE SPECIFICITY, MUTAGENESIS OF 595-GLN--LEU-607.
[7]	"Critical amino acids in the active site of meprin metalloproteinases for substrate and peptide bond specificity." Villa J.P., Bertenshaw G.P., Bond J.S. J. Biol. Chem. 278:42545-42550(2003) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE OF GASTRIN, SUBSTRATE SPECIFICITY, MUTAGENESIS OF LYS-248.
[8]	"Prointerleukin-18 is activated by meprin beta in vitro and in vivo in intestinal inflammation." Banerjee S., Bond J.S. J. Biol. Chem. 283:31371-31377(2008) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE OF IL18.
[9]	"The metalloprotease meprinbeta processes E-cadherin and weakens intercellular adhesion." Huguenin M., Muller E.J., Trachsel-Rosmann S., Oneda B., Ambort D., Sterchi E.E., Lottaz D. PLoS ONE 3:E2153-E2153(2008) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE OF E-CADHERIN.
[10]	"Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases." Hedrich J., Lottaz D., Meyer K., Yiallouros I., Jahnen-Dechent W., Stocker W., Becker-Pauly C. Biochemistry 49:8599-8607(2010) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[11]	"Specific processing of tenascin-C by the metalloprotease meprinbeta neutralizes its inhibition of cell spreading." Ambort D., Brellier F., Becker-Pauly C., Stocker W., Andrejevic-Blant S., Chiquet M., Sterchi E.E. Matrix Biol. 29:31-42(2010) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE OF TNC.
[12]	"Proteomic analyses reveal an acidic prime side specificity for the astacin metalloprotease family reflected by physiological substrates." Becker-Pauly C., Barre O., Schilling O., Auf dem Keller U., Ohler A., Broder C., Schutte A., Kappelhoff R., Stocker W., Overall C.M. Mol. Cell. Proteomics 10:M111.009233.01-M111.009233.19(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, CLEAVAGE OF FGF19; KLK7 AND VGFA.
[13]	"The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin beta and ADAM10." Jefferson T., Auf dem Keller U., Bellac C., Metz V.V., Broder C., Hedrich J., Ohler A., Maier W., Magdolen V., Sterchi E., Bond J.S., Jayakumar A., Traupe H., Chalaris A., Rose-John S., Pietrzik C.U., Postina R., Overall C.M., Becker-Pauly C. Cell. Mol. Life Sci. 70:309-333(2013) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE OF ADAM10, ENZYME REGULATION.
[14]	"Structural basis for the sheddase function of human meprin beta metalloproteinase at the plasma membrane." Arolas J.L., Broder C., Jefferson T., Guevara T., Sterchi E.E., Bode W., Stocker W., Becker-Pauly C., Gomis-Ruth F.X. Proc. Natl. Acad. Sci. U.S.A. 109:16131-16136(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 25-614, GLYCOSYLATION AT ASN-218; ASN-254; ASN-370; ASN-436; ASN-445; ASN-547 AND ASN-592, DISULFIDE BONDS, COFACTOR, ZINC-BINDING SITES, SUBUNIT, SUBCELLULAR LOCATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X81333 mRNA. Translation: CAA57107.1.
AY695931 mRNA. Translation: AAU05377.1.
BC136559 mRNA. Translation: AAI36560.1.
BC144244 mRNA. Translation: AAI44245.1.

IPI

IPI00178015.

PIR

HYHUMB. S49383.

RefSeq

NP_005916.2. NM_005925.2.

UniGene

Hs.194777.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4GWM	X-ray	1.85	A/B	25-614	[»]
4GWN	X-ray	3.00	A	62-614	[»]

ProteinModelPortal

Q16820.

SMR

Q16820. Positions 25-597.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000269202.

Protein family/group databases

MEROPS

M12.004.

PTM databases

PhosphoSite

Q16820.

Polymorphism databases

DMDM

296439304.

Proteomic databases

PaxDb

Q16820.

PRIDE

Q16820.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000269202; ENSP00000269202; ENSG00000141434.

GeneID

4225.

KEGG

hsa:4225.

UCSC

uc002kxj.4. human.

Organism-specific databases

CTD

4225.

GeneCards

GC18P029793.

H-InvDB

HIX0039722.

HGNC

HGNC:7020. MEP1B.

HPA

CAB025850.

MIM

600389. gene.

neXtProt

NX_Q16820.

PharmGKB

PA30754.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG322115.

HOGENOM

HOG000043106.

HOVERGEN

HBG052457.

InParanoid

Q16820.

KO

K08606.

OMA

ETQCPHH.

OrthoDB

EOG408N7Q.

Gene expression databases

Bgee

Q16820.

CleanEx

HS_MEP1B.

Genevestigator

Q16820.

GermOnline

ENSG00000141434. Homo sapiens.

Family and domain databases

Gene3D

3.40.390.10. 1 hit.

InterPro

IPR008985. ConA-like_lec_gl_sf.
IPR000742. EG-like_dom.
IPR000998. MAM_dom.
IPR002083. MATH.
IPR024079. MetalloPept_cat_dom.
IPR008294. Pept_M12A_Meprin.
IPR001506. Peptidase_M12A.
IPR006026. Peptidase_Metallo.
IPR008974. TRAF-like.
[Graphical view]

Pfam

PF01400. Astacin. 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

GenomeRNAi

4225.

NextBio

16675.

SOURCE

Search...

Entry information

Entry name

MEP1B_HUMAN

Accession

Primary (citable) accession number: Q16820
Secondary accession number(s): B7ZM35, B9EGL6, Q670J1

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	May 18, 2010
Last modified:	May 1, 2013
This is version 127 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.