Reviewed, UniProtKB/Swiss-Prot Q5JRX3 (PREP_HUMAN)

Names and origin

Protein names

Recommended name:
    Presequence protease, mitochondrial
      Short name=hPreP
    EC=3.4.24.-
Alternative name(s):
    Pitrilysin metalloproteinase 1
      Short name=Metalloprotease 1
      Short name=hMP1

Gene names

Name:	PITRM1
Synonyms:	KIAA1104, MP1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1037 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	ATP-independent protease that degrades mitochondrial transit peptides after their cleavage. Also degrades other unstructured peptides. Specific for peptides in the range of 10 to 65 residues. Able to degrade amyloid beta A4 (APP) protein when it accumulates in mitochondrion, suggesting a link with Alzheimer disease. Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference. Ref.6
Cofactor	Binds 1 zinc ion per subunit By similarity.
Enzyme regulation	Inhibited by nickel and zinc excess, and slightly activated by manganese.
Subunit structure	Homodimer By similarity.
Subcellular location	Mitochondrion matrix Ref.6.
Tissue specificity	Widely expressed. Expressed at higher level in muscle and heart compared to brain, pancreas, liver, lung and placenta. Ref.1
Post-translational modification	The disulfide bond may lock the enzyme in a closed conformation under oxidized conditions, suggesting that it may participate in redox regulation of the enzyme.
Sequence similarities	Belongs to the peptidase M16 family. PreP subfamily.
Sequence caution	The sequence CAI39997.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Transit peptide
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Disulfide bond
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	proteolysis Ref.6 Inferred from mutant phenotype. Source: UniProtKB
Cellular component	mitochondrial matrix Ref.6 Inferred from direct assay. Source: UniProtKB nucleus Inferred from direct assay. Source: HPA
Molecular function	enzyme activator activity Traceable author statement. Source: ProtInc metalloendopeptidase activity Ref.6 Inferred from mutant phenotype. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q5JRX3-1)

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: Q5JRX3-2)

The sequence of this isoform differs from the canonical sequence as follows:
     664-664: Q → QV

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – 15	15	Mitochondrion
	Chain	16 – 1037	1022	Presequence protease, mitochondrial		PRO_0000249931
Sites
	Active site	107	1	Proton acceptor
	Metal binding	104	1	Zinc; catalytic By similarity
	Metal binding	108	1	Zinc; catalytic By similarity
	Metal binding	205	1	Zinc; catalytic By similarity
Amino acid modifications
	Disulfide bond	119 ↔ 556		Probable
Natural variations
	Alternative sequence	664	1	Q → QV in isoform 2.		VSP_020597
	Natural variant	8	1	Q → R: dbSNP rs11818724. Ref.4		VAR_027517
	Natural variant	145	1	L → V: dbSNP rs9423502. Ref.4		VAR_027518
	Natural variant	169	1	F → S: dbSNP rs3814596. Ref.1		VAR_027519
	Natural variant	328	1	V → I: dbSNP rs4242746. Ref.1 Ref.3		VAR_027520
	Natural variant	397	1	V → A: dbSNP rs3182535. Ref.1 Ref.3		VAR_027521
	Natural variant	516	1	Q → H: dbSNP rs3765101.		VAR_027522
	Natural variant	554	1	A → D: dbSNP rs12248937.		VAR_057059
	Natural variant	621	1	V → I: dbSNP rs2388556. Ref.1		VAR_027523
	Natural variant	805	1	R → Q: dbSNP rs34837384.		VAR_057060
	Natural variant	952	1	I → M: dbSNP rs2279219.		VAR_027524
	Natural variant	963	1	V → I: dbSNP rs17849904. Ref.4		VAR_027525
	Natural variant	969	1	P → L: dbSNP rs2279218.		VAR_027526
	Natural variant	1037	1	R → Q: dbSNP rs6901. Ref.1 Ref.3		VAR_027527
Experimental info
	Mutagenesis	107	1	E → Q: Loss of function. Ref.6
	Mutagenesis	119	1	C → S: Still active under oxidizing conditions. Ref.6
	Sequence conflict	121	1	D → N in AAC67244. Ref.1
	Sequence conflict	211	1	T → V in CAI40001. Ref.3
	Sequence conflict	212	1	D → N in CAI40001. Ref.3
	Sequence conflict	373	1	D → E in AAC67244. Ref.1
	Sequence conflict	418 – 420	3	KGF → TRI in AAC67244. Ref.1
	Sequence conflict	883 – 884	2	LK → FE in AAH95422. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified September 19, 2006. Version 2. Checksum: 7FD1A4AA2BBEF9F5	FASTA	1,037	117,455
	10 20 30 40 50 60 MWRCGGRQGL CVLRRLSGGH AHHRAWRWNS NRACERALQY KLGDKIHGFT VNQVTSVPEL 70 80 90 100 110 120 FLTAVKLTHD DTGARYLHLA REDTNNLFSV QFRTTPMDST GVPHILEHTV LCGSQKYPCR 130 140 150 160 170 180 DPFFKMLNRS LSTFMNAFTA SDYTLYPFST QNPKDFQNLL SVYLDATFFP CLRELDFWQE 190 200 210 220 230 240 GWRLEHENPS DPQTPLVFKG VVFNEMKGAF TDNERIFSQH LQNRLLPDHT YSVVSGGDPL 250 260 270 280 290 300 CIPELTWEQL KQFHATHYHP SNARFFTYGN FPLEQHLKQI HEEALSKFQK IEPSTVVPAQ 310 320 330 340 350 360 TPWDKPREFQ ITCGPDSFAT DPSKQTTVSV SFLLPDITDT FEAFTLSLLS SLLTSGPNSP 370 380 390 400 410 420 FYKALIESGL GTDFSPDVGY NGYTREAYFS VGLQGIVEKD IETVRSLIDR TIDEVVEKGF 430 440 450 460 470 480 EDDRIEALLH KIEIQMKHQS TSFGLMLTSY IASCWNHDGD PVELLKLGNQ LAKFRQCLQE 490 500 510 520 530 540 NPKFLQEKVK QYFKNNQHKL TLSMRPDDKY HEKQAQVEAT KLKQKVEALS PGDRQQIYEK 550 560 570 580 590 600 GLELRSQQSK PQDASCLPAL KVSDIEPTIP VTELDVVLTA GDIPVQYCAQ PTNGMVYFRA 610 620 630 640 650 660 FSSLNTLPEE LRPYVPLFCS VLTKLGCGLL DYREQAQQIE LKTGGMSASP HVLPDDSHMD 670 680 690 700 710 720 TYEQGVLFSS LCLDRNLPDM MQLWSEIFNN PCFEEEEHFK VLVKMTAQEL ANGIPDSGHL 730 740 750 760 770 780 YASIRAGRTL TPAGDLQETF SGMDQVRLMK RIAEMTDIKP ILRKLPRIKK HLLNGDNMRC 790 800 810 820 830 840 SVNATPQQMP QTEKAVEDFL RSIGRSKKER RPVRPHTVEK PVPSSSGGDA HVPHGSQVIR 850 860 870 880 890 900 KLVMEPTFKP WQMKTHFLMP FPVNYVGECI RTVPYTDPDH ASLKILARLM TAKFLHTEIR 910 920 930 940 950 960 EKGGAYGGGA KLSHNGIFTL YSYRDPNTIE TLQSFGKAVD WAKSGKFTQQ DIDEAKLSVF 970 980 990 1000 1010 1020 STVDAPVAPS DKGMDHFLYG LSDEMKQAHR EQLFAVSHDK LLAVSDRYLG TGKSTHGLAI 1030 LGPENPKIAK DPSWIIR
	Isoform 2. Checksum: 00FC3A380E66D520	FASTA	1,038	117,554
	10 20 30 40 50 60 MWRCGGRQGL CVLRRLSGGH AHHRAWRWNS NRACERALQY KLGDKIHGFT VNQVTSVPEL 70 80 90 100 110 120 FLTAVKLTHD DTGARYLHLA REDTNNLFSV QFRTTPMDST GVPHILEHTV LCGSQKYPCR 130 140 150 160 170 180 DPFFKMLNRS LSTFMNAFTA SDYTLYPFST QNPKDFQNLL SVYLDATFFP CLRELDFWQE 190 200 210 220 230 240 GWRLEHENPS DPQTPLVFKG VVFNEMKGAF TDNERIFSQH LQNRLLPDHT YSVVSGGDPL 250 260 270 280 290 300 CIPELTWEQL KQFHATHYHP SNARFFTYGN FPLEQHLKQI HEEALSKFQK IEPSTVVPAQ 310 320 330 340 350 360 TPWDKPREFQ ITCGPDSFAT DPSKQTTVSV SFLLPDITDT FEAFTLSLLS SLLTSGPNSP 370 380 390 400 410 420 FYKALIESGL GTDFSPDVGY NGYTREAYFS VGLQGIVEKD IETVRSLIDR TIDEVVEKGF 430 440 450 460 470 480 EDDRIEALLH KIEIQMKHQS TSFGLMLTSY IASCWNHDGD PVELLKLGNQ LAKFRQCLQE 490 500 510 520 530 540 NPKFLQEKVK QYFKNNQHKL TLSMRPDDKY HEKQAQVEAT KLKQKVEALS PGDRQQIYEK 550 560 570 580 590 600 GLELRSQQSK PQDASCLPAL KVSDIEPTIP VTELDVVLTA GDIPVQYCAQ PTNGMVYFRA 610 620 630 640 650 660 FSSLNTLPEE LRPYVPLFCS VLTKLGCGLL DYREQAQQIE LKTGGMSASP HVLPDDSHMD 670 680 690 700 710 720 TYEQVGVLFS SLCLDRNLPD MMQLWSEIFN NPCFEEEEHF KVLVKMTAQE LANGIPDSGH 730 740 750 760 770 780 LYASIRAGRT LTPAGDLQET FSGMDQVRLM KRIAEMTDIK PILRKLPRIK KHLLNGDNMR 790 800 810 820 830 840 CSVNATPQQM PQTEKAVEDF LRSIGRSKKE RRPVRPHTVE KPVPSSSGGD AHVPHGSQVI 850 860 870 880 890 900 RKLVMEPTFK PWQMKTHFLM PFPVNYVGEC IRTVPYTDPD HASLKILARL MTAKFLHTEI 910 920 930 940 950 960 REKGGAYGGG AKLSHNGIFT LYSYRDPNTI ETLQSFGKAV DWAKSGKFTQ QDIDEAKLSV 970 980 990 1000 1010 1020 FSTVDAPVAP SDKGMDHFLY GLSDEMKQAH REQLFAVSHD KLLAVSDRYL GTGKSTHGLA 1030 ILGPENPKIA KDPSWIIR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning, expression, and characterization of human metalloprotease 1: a novel member of the pitrilysin family of metalloendoproteases." Mzhavia N., Berman Y.L., Qian Y., Yan L., Devi L.A. DNA Cell Biol. 18:369-380(1999) [PubMed: 10360838] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY, VARIANTS SER-169; ILE-328; ALA-397; ILE-621 AND GLN-1037.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Placenta.
[3]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed: 15164054] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANTS ILE-328; ALA-397 AND GLN-1037.
[4]	"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] (ISOFORM 1), VARIANTS ARG-8; VAL-145 AND ILE-963. Tissue: Brain, Lung and Testis.
[5]	"Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro." Kikuno R., Nagase T., Ishikawa K., Hirosawa M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 6:197-205(1999) [PubMed: 10470851] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 402-1037 (ISOFORM 1). Tissue: Brain.
[6]	"Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP." Falkevall A., Alikhani N., Bhushan S., Pavlov P.F., Busch K., Johnson K.A., Eneqvist T., Tjernberg L., Ankarcrona M., Glaser E. J. Biol. Chem. 281:29096-29104(2006) [PubMed: 16849325] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, DISULFIDE BOND, MUTAGENESIS OF GLU-107 AND CYS-119.
[7]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[8]	"Mammalian pitrilysin: substrate specificity and mitochondrial targeting." Chow K.M., Gakh O., Payne I.C., Juliano M.A., Juliano L., Isaya G., Hersh L.B. Biochemistry 48:2868-2877(2009) [PubMed: 19196155] [Abstract] Cited for: TRANSIT PEPTIDE, ENZYME REGULATION, SUBSTRATE SPECIFICITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF061243 mRNA. Translation: AAC67244.1. AK002061 mRNA. Translation: BAG51008.1. AL451164 Genomic DNA. Translation: CAI40001.1. AL451164 Genomic DNA. Translation: CAI39997.1. Sequence problems. BC001150 mRNA. Translation: AAH01150.1. Different initiation. BC005025 mRNA. Translation: AAH05025.1. BC095422 mRNA. Translation: AAH95422.1. BC111987 mRNA. Translation: AAI11988.1. BC113369 mRNA. Translation: AAI13370.1. AB029027 mRNA. Translation: BAA83056.2.
IPI	IPI00787827. IPI00952680.
RefSeq	NP_055704.2.
UniGene	Hs.528300
3D structure databases
HSSP	HSSP built from PDB template 2FGE based on UniProtKB Q9LJL3.
ModBase	Search...
Protein-protein interaction databases
STRING	Q5JRX3.
Protein family/group databases
MEROPS	M16.009.
Proteomic databases
PRIDE	Q5JRX3.
Genome annotation databases
Ensembl	ENST00000224949; ENSP00000224949; ENSG00000107959; Homo sapiens. [Genome view]
GeneID	10531.
KEGG	hsa:10531.
UCSC	uc001igt.1. human.
Organism-specific databases
CTD	10531.
GeneCards	GC10M003169.
HGNC	HGNC:17663. PITRM1.
HPA	HPA006753. HPA006754.
PharmGKB	PA134902269.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG13299.
HOVERGEN	Q5JRX3.
PhylomeDB	Q5JRX3.
Gene expression databases
ArrayExpress	Q5JRX3.
Bgee	Q5JRX3.
CleanEx	HS_PITRM1.
Genevestigator	Q5JRX3.
GermOnline	ENSG00000107959. Homo sapiens.
Family and domain databases
InterPro	IPR011249. Metalloenz_metal-bd. IPR011237. Pept_M16_core. IPR011765. Pept_M16_N. IPR007863. Peptidase_M16_C. IPR013578. Peptidase_M16C_assoc. [Graphical view]
Gene3D	G3DSA:3.30.830.10. Pept_M16_core. 1 hit.
Pfam	PF08367. M16C_assoc. 1 hit. PF00675. Peptidase_M16. 1 hit. PF05193. Peptidase_M16_C. 2 hits. [Graphical view]
PROSITE	PS00143. INSULINASE. False negative. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	39957.

Entry information

Entry name

PREP_HUMAN

Accession

Primary (citable) accession number: Q5JRX3
Secondary accession number(s): B3KMJ6 , O95204, Q2M2G6, Q4VBR1, Q5JRW7, Q7L5Z7, Q9BSI6, Q9BVJ5, Q9UPP8

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 19, 2006
Last sequence update:	September 19, 2006
Last modified:	February 9, 2010
This is version 53 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.