Q9JLI3 (MMEL1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Membrane metallo-endopeptidase-like 1
EC=3.4.24.11

Alternative name(s):
NEP2(m)
Neprilysin II
Short name=NEPII
Neprilysin-2
Short name=NEP2
Short name=NL2
Neprilysin-like 1
Short name=NL-1
Neprilysin-like peptidase
Short name=NEPLP
Soluble secreted endopeptidase

Cleaved into the following chain:

1. Membrane metallo-endopeptidase-like 1, soluble form
   Alternative name(s):
   Neprilysin-2 secreted
   Short name=NEP2(s)

Gene names

Name:	Mmel1
Synonyms:	Nep2, Nl1, Sep

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	765 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	Metalloprotease involved in sperm function, possibly by modulating the processes of fertilization and early embryonic development. Degrades a broad variety of small peptides with a preference for peptides shorter than 3 kDa containing neutral bulky aliphatic or aromatic amino acid residues. Shares the same substrate specificity with MME and cleaves peptides at the same amide bond. Ref.1 Ref.3
Catalytic activity	Preferential cleavage of polypeptides between hydrophobic residues, particularly with Phe or Tyr at P1'.
Cofactor	Binds 1 zinc ion per subunit By similarity.
Enzyme regulation	Inhibited by thiorphan and phosphoramidon. Ref.3
Subcellular location	Membrane; Single-pass type II membrane protein. Secreted. Note: A secreted form produced by proteollytic cleavage also exists. Ref.1
Tissue specificity	Highly expressed in testis. Also expressed in ovary. Weakly or not expressed in brain, lung, heart, liver, kidney, adrenal gland and intestine. Ref.1
Post-translational modification	N-glycosylated. Ref.1 Ref.2
Disruption phenotype	Mice are viable and develop normally. However, males produce smaller litters, indicating specific male fertility problems. Ref.5
Sequence similarities	Belongs to the peptidase M13 family.
Biophysicochemical properties	Kinetic parameters: KM=18 µM for D-Ala(2)-Leu(5)-enkephalin Ref.2
Sequence caution	The sequence BAE32538.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Cellular component	Membrane Secreted
Coding sequence diversity	Alternative splicing
Domain	Coiled coil Signal-anchor Transmembrane Transmembrane helix
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Disulfide bond Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	proteolysis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	Golgi apparatus Inferred from direct assay Ref.1. Source: MGI endoplasmic reticulum Inferred from direct assay Ref.1. Source: MGI extracellular space Traceable author statement Ref.1. Source: MGI integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	metalloendopeptidase activity Inferred from sequence or structural similarity Ref.1. Source: MGI zinc ion binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9JLI3-1)

Also known as: Beta;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9JLI3-2)

Also known as: Alpha; Delta;

The sequence of this isoform differs from the canonical sequence as follows:
     41-63: Missing.

Isoform 3 (identifier: Q9JLI3-3)

Also known as: Gamma;

The sequence of this isoform differs from the canonical sequence as follows:
     41-63: Missing.
     330-330: F → FGLKDRVSLCSPGCPGTHSVDQAGLELGNPPASDSRVL

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 765	765	Membrane metallo-endopeptidase-like 1		PRO_0000248417
	Chain	63 – 765	703	Membrane metallo-endopeptidase-like 1, soluble form Probable		PRO_0000248418
Regions
	Topological domain	1 – 19	19	Cytoplasmic Potential
	Transmembrane	20 – 40	21	Helical; Signal-anchor for type II membrane protein; Potential
	Topological domain	41 – 765	725	Lumenal Potential
	Coiled coil	523 – 549	27	Potential
Sites
	Active site	606	1	By similarity
	Active site	666	1	Proton donor By similarity
	Metal binding	599	1	Zinc; catalytic By similarity
	Metal binding	603	1	Zinc; catalytic By similarity
	Metal binding	662	1	Zinc; catalytic By similarity
	Binding site	121	1	Substrate carboxyl By similarity
	Site	62 – 63	2	Cleavage Probable
Amino acid modifications
	Glycosylation	163	1	N-linked (GlcNAc...) Potential
	Glycosylation	279	1	N-linked (GlcNAc...) Potential
	Glycosylation	303	1	N-linked (GlcNAc...) Potential
	Glycosylation	336	1	N-linked (GlcNAc...) Potential
	Glycosylation	694	1	N-linked (GlcNAc...) Potential
	Disulfide bond	75 ↔ 80		By similarity
	Disulfide bond	98 ↔ 750		By similarity
	Disulfide bond	106 ↔ 710		By similarity
	Disulfide bond	161 ↔ 425		By similarity
	Disulfide bond	636 ↔ 762		By similarity
Natural variations
	Alternative sequence	41 – 63	23	Missing in isoform 2 and isoform 3.		VSP_020290
	Alternative sequence	330	1	F → FGLKDRVSLCSPGCPGTHSV DQAGLELGNPPASDSRVL in isoform 3.		VSP_020291
Experimental info
	Mutagenesis	62 – 63	2	KR → NG: Abolishes formation the soluble form. Ref.2
	Sequence conflict	189	1	M → L in AAF13152. Ref.1
	Sequence conflict	189	1	M → L in AAF13153. Ref.1
	Sequence conflict	264	1	L → P in AAF13152. Ref.1
	Sequence conflict	264	1	L → P in AAF13153. Ref.1
	Sequence conflict	659	1	T → S in AAF13152. Ref.1
	Sequence conflict	659	1	T → S in AAF13153. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Beta) [UniParc]. Last modified October 1, 2000. Version 1. Checksum: D3662F1CE5B957F7	FASTA	765	88,700
	10 20 30 40 50 60 MVERAGWCRK KSPGFVEYGL MVLLLLLLGA IVTLGVFYSI GKQLPLLTSL LHFSWDERTV 70 80 90 100 110 120 VKRALRDSSL KSDICTTPSC VIAAARILEN MDQSRNPCEN FYQYACGGWL RHHVIPETNS 130 140 150 160 170 180 RYSVFDILRD ELEVILKGVL EDSTSQHRPA VEKAKTLYRS CMNQSVIEKR DSEPLLSVLK 190 200 210 220 230 240 MVGGWPVAMD KWNETMGLKW ELERQLAVLN SQFNRRVLID LFIWNDDQNS SRHVIYIDQP 250 260 270 280 290 300 TLGMPSREYY FQEDNNHKVR KAYLEFMTSV ATMLRKDQNL SKESAMVREE MAEVLELETH 310 320 330 340 350 360 LANATVPQEK RHDVTALYHR MDLMELQERF GLKGFNWTLF IQNVLSSVEV ELFPDEEVVV 370 380 390 400 410 420 YGIPYLENLE DIIDSYSART MQNYLVWRLV LDRIGSLSQR FKEARVDYRK ALYGTTVEEV 430 440 450 460 470 480 RWRECVSYVN SNMESAVGSL YIKRAFSKDS KSTVRELIEK IRSVFVDNLD ELNWMDEESK 490 500 510 520 530 540 KKAQEKAMNI REQIGYPDYI LEDNNKHLDE EYSSLTFYED LYFENGLQNL KNNAQRSLKK 550 560 570 580 590 600 LREKVDQNLW IIGAAVVNAF YSPNRNQIVF PAGILQPPFF SKDQPQSLNF GGIGMVIGHE 610 620 630 640 650 660 ITHGFDDNGR NFDKNGNMLD WWSNFSARHF QQQSQCMIYQ YGNFSWELAD NQNVNGFSTL 670 680 690 700 710 720 GENIADNGGV RQAYKAYLRW LADGGKDQRL PGLNLTYAQL FFINYAQVWC GSYRPEFAVQ 730 740 750 760 SIKTDVHSPL KYRVLGSLQN LPGFSEAFHC PRGSPMHPMK RCRIW
	Isoform 2 (Alpha) (Delta) [UniParc]. Checksum: 4A44EAD211B2499F	FASTA	742	85,994
	10 20 30 40 50 60 MVERAGWCRK KSPGFVEYGL MVLLLLLLGA IVTLGVFYSI ALRDSSLKSD ICTTPSCVIA 70 80 90 100 110 120 AARILENMDQ SRNPCENFYQ YACGGWLRHH VIPETNSRYS VFDILRDELE VILKGVLEDS 130 140 150 160 170 180 TSQHRPAVEK AKTLYRSCMN QSVIEKRDSE PLLSVLKMVG GWPVAMDKWN ETMGLKWELE 190 200 210 220 230 240 RQLAVLNSQF NRRVLIDLFI WNDDQNSSRH VIYIDQPTLG MPSREYYFQE DNNHKVRKAY 250 260 270 280 290 300 LEFMTSVATM LRKDQNLSKE SAMVREEMAE VLELETHLAN ATVPQEKRHD VTALYHRMDL 310 320 330 340 350 360 MELQERFGLK GFNWTLFIQN VLSSVEVELF PDEEVVVYGI PYLENLEDII DSYSARTMQN 370 380 390 400 410 420 YLVWRLVLDR IGSLSQRFKE ARVDYRKALY GTTVEEVRWR ECVSYVNSNM ESAVGSLYIK 430 440 450 460 470 480 RAFSKDSKST VRELIEKIRS VFVDNLDELN WMDEESKKKA QEKAMNIREQ IGYPDYILED 490 500 510 520 530 540 NNKHLDEEYS SLTFYEDLYF ENGLQNLKNN AQRSLKKLRE KVDQNLWIIG AAVVNAFYSP 550 560 570 580 590 600 NRNQIVFPAG ILQPPFFSKD QPQSLNFGGI GMVIGHEITH GFDDNGRNFD KNGNMLDWWS 610 620 630 640 650 660 NFSARHFQQQ SQCMIYQYGN FSWELADNQN VNGFSTLGEN IADNGGVRQA YKAYLRWLAD 670 680 690 700 710 720 GGKDQRLPGL NLTYAQLFFI NYAQVWCGSY RPEFAVQSIK TDVHSPLKYR VLGSLQNLPG 730 740 FSEAFHCPRG SPMHPMKRCR IW
	Isoform 3 (Gamma) [UniParc]. Checksum: 5E48CA530828584B	FASTA	779	89,710
	10 20 30 40 50 60 MVERAGWCRK KSPGFVEYGL MVLLLLLLGA IVTLGVFYSI ALRDSSLKSD ICTTPSCVIA 70 80 90 100 110 120 AARILENMDQ SRNPCENFYQ YACGGWLRHH VIPETNSRYS VFDILRDELE VILKGVLEDS 130 140 150 160 170 180 TSQHRPAVEK AKTLYRSCMN QSVIEKRDSE PLLSVLKMVG GWPVAMDKWN ETMGLKWELE 190 200 210 220 230 240 RQLAVLNSQF NRRVLIDLFI WNDDQNSSRH VIYIDQPTLG MPSREYYFQE DNNHKVRKAY 250 260 270 280 290 300 LEFMTSVATM LRKDQNLSKE SAMVREEMAE VLELETHLAN ATVPQEKRHD VTALYHRMDL 310 320 330 340 350 360 MELQERFGLK DRVSLCSPGC PGTHSVDQAG LELGNPPASD SRVLGLKGFN WTLFIQNVLS 370 380 390 400 410 420 SVEVELFPDE EVVVYGIPYL ENLEDIIDSY SARTMQNYLV WRLVLDRIGS LSQRFKEARV 430 440 450 460 470 480 DYRKALYGTT VEEVRWRECV SYVNSNMESA VGSLYIKRAF SKDSKSTVRE LIEKIRSVFV 490 500 510 520 530 540 DNLDELNWMD EESKKKAQEK AMNIREQIGY PDYILEDNNK HLDEEYSSLT FYEDLYFENG 550 560 570 580 590 600 LQNLKNNAQR SLKKLREKVD QNLWIIGAAV VNAFYSPNRN QIVFPAGILQ PPFFSKDQPQ 610 620 630 640 650 660 SLNFGGIGMV IGHEITHGFD DNGRNFDKNG NMLDWWSNFS ARHFQQQSQC MIYQYGNFSW 670 680 690 700 710 720 ELADNQNVNG FSTLGENIAD NGGVRQAYKA YLRWLADGGK DQRLPGLNLT YAQLFFINYA 730 740 750 760 770 QVWCGSYRPE FAVQSIKTDV HSPLKYRVLG SLQNLPGFSE AFHCPRGSPM HPMKRCRIW

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular identification and characterization of novel membrane-bound metalloprotease, the soluble secreted form of which hydrolyzes a variety of vasoactive peptides." Ikeda K., Emoto N., Raharjo S.B., Nurhantari Y., Saiki K., Yokoyama M., Matsuo M. J. Biol. Chem. 274:32469-32477(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, GLYCOSYLATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY. Tissue: Testis.
[2]	"Molecular cloning and biochemical characterization of a new mouse testis soluble zinc-metallopeptidase of the neprilysin family." Ghaddar G., Ruchon A.F., Carpentier M., Marcinkiewicz M., Seidah N.G., Crine P., DesGroseillers L., Boileau G. Biochem. J. 347:419-429(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), GLYCOSYLATION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF 62-LYS-ARG-63. Tissue: Testis.
[3]	"Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases." Shirotani K., Tsubuki S., Iwata N., Takaki Y., Harigaya W., Maruyama K., Kiryu-Seo S., Kiyama H., Iwata H., Tomita T., Iwatsubo T., Saido T.C. J. Biol. Chem. 276:21895-21901(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, ENZYME REGULATION.
[4]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 64-765. Strain: NOD.
[5]	"Reduced fertility in male mice deficient in the zinc metallopeptidase NL1." Carpentier M., Guillemette C., Bailey J.L., Boileau G., Jeannotte L., DesGroseillers L., Charron J. Mol. Cell. Biol. 24:4428-4437(2004) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF157105 mRNA. Translation: AAF13152.1. AF157106 mRNA. Translation: AAF13153.1. AF176569 mRNA. Translation: AAF69247.1. AF302075 mRNA. Translation: AAG18446.1. AF302076 mRNA. Translation: AAG18447.1. AF302077 mRNA. Translation: AAG18448.1. AK154366 mRNA. Translation: BAE32538.1. Different initiation.
IPI	IPI00112412. IPI00317343. IPI00648163.
RefSeq	NP_038811.2. NM_013783.2.
UniGene	Mm.116944.
3D structure databases
HSSP	HSSP built from PDB template 1DMT based on UniProtKB P08473.
ProteinModelPortal	Q9JLI3.
SMR	Q9JLI3. Positions 74-765.
ModBase	Search...
Protein family/group databases
MEROPS	M13.008.
PTM databases
PhosphoSite	Q9JLI3.
Proteomic databases
PaxDb	Q9JLI3.
PRIDE	Q9JLI3.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	27390.
KEGG	mmu:27390.
UCSC	uc012dqm.1. mouse.
Organism-specific databases
CTD	79258.
MGI	MGI:1351603. Mmel1.
Phylogenomic databases
eggNOG	COG3590.
HOGENOM	HOG000245574.
HOVERGEN	HBG005554.
KO	K08635.
OrthoDB	EOG4GXFM5.
Gene expression databases
ArrayExpress	Q9JLI3.
Bgee	Q9JLI3.
CleanEx	MM_MMEL1.
Genevestigator	Q9JLI3.
GermOnline	ENSMUSG00000058183. Mus musculus.
Family and domain databases
Gene3D	3.40.390.10. 2 hits.
InterPro	IPR024079. MetalloPept_cat_dom. IPR000718. Peptidase_M13. IPR018497. Peptidase_M13_C. IPR008753. Peptidase_M13_N. [Graphical view]
PANTHER	PTHR11733. PTHR11733. 1 hit.
Pfam	PF01431. Peptidase_M13. 1 hit. PF05649. Peptidase_M13_N. 1 hit. [Graphical view]
PRINTS	PR00786. NEPRILYSIN.
PROSITE	PS00142. ZINC_PROTEASE. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	305354.
SOURCE	Search...

Entry information

Entry name

MMEL1_MOUSE

Accession

Primary (citable) accession number: Q9JLI3
Secondary accession number(s): Q3U495 , Q9ERK2, Q9ERK3, Q9QZV6, Q9QZV7

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 5, 2006
Last sequence update:	October 1, 2000
Last modified:	April 3, 2013
This is version 79 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program