Q86T82 (UBP37_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ubiquitin carboxyl-terminal hydrolase 37
EC=3.4.19.12

Alternative name(s):
Deubiquitinating enzyme 37
Ubiquitin thioesterase 37
Ubiquitin-specific-processing protease 37

Gene names

Name:	USP37
Synonyms:	KIAA1594

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	979 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Deubiquitinase that antagonizes the anaphase-promoting complex (APC/C) during G1/S transition by mediating deubiquitination of cyclin-A (CCNA1 and CCNA2), thereby promoting S phase entry. Specifically mediates deubiquitination of 'Lys-11'-linked polyubiquitin chains, a specific ubiquitin-linkage type mediated by the APC/C complex. Also mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains in vitro. Phosphorylation at Ser-628 during G1/S phase maximizes the deubiquitinase activity, leading to prevent degradation of cyclin-A (CCNA1 and CCNA2). Ref.8
Catalytic activity	Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal). Ref.6
Subunit structure	Interacts with FZR1/CDH1. Ref.8
Tissue specificity	Expressed in brain and prostate. Ref.6
Developmental stage	Induced in G1 phase, accumulates at G1/S transition, and degraded in late mitosis following ubiquitination and degradation by the APC(CDH1) complex. Ref.8
Induction	Induced by E2F transcription factors in G1. Ref.8
Domain	The KEN box 3 is required for interaction with FZR1/CDH1 and is essential for APC(CDH1)-mediated ubiquitination. Ref.8
Post-translational modification	Polyubiquitinated via 'Lys-11'-linked ubiquitin by the APC(CDH1) complex during late mitosis, leading to its degradation. Able to mediate auto-deubiquitination. Phosphorylated at Ser-628 by CDK2 during G1/S phase but not during mitosis; phosphorylation at Ser-628 is required for deubiquitinase activity. Also polyubiquitinated during early G1 phase, without leading to degradation. Ref.8
Sequence similarities	Belongs to the peptidase C19 family. Contains 3 UIM (ubiquitin-interacting motif) repeats.
Sequence caution	The sequence AAY14887.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Biological process	Cell cycle Cell division Mitosis Ubl conjugation pathway
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1/S transition of mitotic cell cycle Inferred from direct assay Ref.8. Source: UniProtKB cell division Inferred from electronic annotation. Source: UniProtKB-KW mitosis Inferred from electronic annotation. Source: UniProtKB-KW protein K11-linked deubiquitination Inferred from direct assay Ref.8. Source: UniProtKB protein K48-linked deubiquitination Inferred from direct assay Ref.8. Source: UniProtKB ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular_component	nucleus Inferred from direct assay. Source: LIFEdb
Molecular_function	cysteine-type endopeptidase activity Inferred from direct assay Ref.8. Source: UniProtKB ubiquitin thiolesterase activity Inferred from electronic annotation. Source: InterPro ubiquitin-specific protease activity Inferred from direct assay Ref.8. Source: UniProtKB
Complete GO annotation...

Alternative products

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

Isoform 1 (identifier: Q86T82-1)

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: Q86T82-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-72: Missing.
     612-634: ISRPLKASQMVNSCITSPSTPSK → M

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 979

979

Ubiquitin carboxyl-terminal hydrolase 37

PRO_0000080667

Regions

Repeat

704 – 723

20

UIM 1

Repeat

806 – 825

20

UIM 2

Repeat

828 – 847

20

UIM 3

Motif

32 – 34

3

KEN box 1

Motif

71 – 79

9

D-box 1

Motif

96 – 105

10

D-box 2

Motif

160 – 168

9

D-box 3

Motif

221 – 223

3

KEN box 2

Motif

782 – 784

3

KEN box 3

Sites

Active site

350

1

Nucleophile Probable

Active site

906

1

Proton acceptor By similarity

Amino acid modifications

Modified residue

213

1

Phosphoserine By similarity

Modified residue

628

1

Phosphoserine; by CDK2 Ref.8

Modified residue

650

1

Phosphoserine Ref.7

Modified residue

652

1

Phosphoserine Ref.7

Natural variations

Alternative sequence

1 – 72

72

Missing in isoform 2.

VSP_041740

Alternative sequence

612 – 634

23

ISRPL…STPSK → M in isoform 2.

VSP_041741

Natural variant

979

1

L → S. Ref.1 Ref.3 Ref.4 Ref.5
Corresponds to variant rs6436058 [ dbSNP | Ensembl ].

VAR_059752

Experimental info

Mutagenesis

32 – 34

3

KEN → AAA: No effect. Ref.8

Mutagenesis

71 – 74

4

RLML → ALMA: No effect.

Mutagenesis

96 – 99

4

RLFL → ALFA: No effect.

Mutagenesis

160 – 163

4

RKVL → AKVA: No effect.

Mutagenesis

221 – 223

3

KEN → AAA: No effect. Ref.8

Mutagenesis

350

1

C → S: Abolishes deubiquitinase activity. Ref.8

Mutagenesis

628

1

S → A: Abolishes phosphorylation by CDK2, leading to lower deubiquitinase activity. Ref.8

Mutagenesis

782 – 784

3

KEN → AAA: Impaired interaction with FZR1/CDH1 and subsequent ubiquitination. Ref.8

Sequence conflict

223 – 224

2

ND → DG in CAD89955. Ref.1

Sequence conflict

345

1

N → K in CAD97970. Ref.1

Sequence conflict

456

1

V → I in CAD89955. Ref.1

Sequence conflict

552

1

F → I in AAI44250. Ref.4

Sequence conflict

567

1

S → I in AAI44253. Ref.4

Sequence conflict

576

1

N → Y in AAI44253. Ref.4

Sequence conflict

731

1

K → E in CAD97970. Ref.1

Sequence conflict

905

1

G → D in CAD97970. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

979

Helix Strand Turn

Details...

Beta strand

5 – 14

10

Turn

15 – 17

3

Beta strand

23 – 32

10

Beta strand

35 – 42

8

Beta strand

49 – 52

4

Turn

54 – 56

3

Beta strand

57 – 64

8

Beta strand

69 – 76

8

Beta strand

81 – 88

8

Helix

89 – 103

15

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 13, 2010. Version 2. Checksum: 9F47F06A744EA449	FASTA	979	110,170
	10 20 30 40 50 60 MSPLKIHGPI RIRSMQTGIT KWKEGSFEIV EKENKVSLVV HYNTGGIPRI FQLSHNIKNV 70 80 90 100 110 120 VLRPSGAKQS RLMLTLQDNS FLSIDKVPSK DAEEMRLFLD AVHQNRLPAA MKPSQGSGSF 130 140 150 160 170 180 GAILGSRTSQ KETSRQLSYS DNQASAKRGS LETKDDIPFR KVLGNPGRGS IKTVAGSGIA 190 200 210 220 230 240 RTIPSLTSTS TPLRSGLLEN RTEKRKRMIS TGSELNEDYP KENDSSSNNK AMTDPSRKYL 250 260 270 280 290 300 TSSREKQLSL KQSEENRTSG LLPLQSSSFY GSRAGSKEHS SGGTNLDRTN VSSQTPSAKR 310 320 330 340 350 360 SLGFLPQPVP LSVKKLRCNQ DYTGWNKPRV PLSSHQQQQL QGFSNLGNTC YMNAILQSLF 370 380 390 400 410 420 SLQSFANDLL KQGIPWKKIP LNALIRRFAH LLVKKDICNS ETKKDLLKKV KNAISATAER 430 440 450 460 470 480 FSGYMQNDAH EFLSQCLDQL KEDMEKLNKT WKTEPVSGEE NSPDISATRA YTCPVITNLE 490 500 510 520 530 540 FEVQHSIICK ACGEIIPKRE QFNDLSIDLP RRKKPLPPRS IQDSLDLFFR AEELEYSCEK 550 560 570 580 590 600 CGGKCALVRH KFNRLPRVLI LHLKRYSFNV ALSLNNKIGQ QVIIPRYLTL SSHCTENTKP 610 620 630 640 650 660 PFTLGWSAHM AISRPLKASQ MVNSCITSPS TPSKKFTFKS KSSLALCLDS DSEDELKRSV 670 680 690 700 710 720 ALSQRLCEML GNEQQQEDLE KDSKLCPIEP DKSELENSGF DRMSEEELLA AVLEISKRDA 730 740 750 760 770 780 SPSLSHEDDD KPTSSPDTGF AEDDIQEMPE NPDTMETEKP KTITELDPAS FTEITKDCDE 790 800 810 820 830 840 NKENKTPEGS QGEVDWLQQY DMEREREEQE LQQALAQSLQ EQEAWEQKED DDLKRATELS 850 860 870 880 890 900 LQEFNNSFVD ALGSDEDSGN EDVFDMEYTE AEAEELKRNA ETGNLPHSYR LISVVSHIGS 910 920 930 940 950 960 TSSSGHYISD VYDIKKQAWF TYNDLEVSKI QEAAVQSDRD RSGYIFFYMH KEIFDELLET 970 EKNSQSLSTE VGKTTRQAL
	Isoform 2 [UniParc]. Checksum: D5D5E4077F1155B4	FASTA	885	99,752
	10 20 30 40 50 60 MLTLQDNSFL SIDKVPSKDA EEMRLFLDAV HQNRLPAAMK PSQGSGSFGA ILGSRTSQKE 70 80 90 100 110 120 TSRQLSYSDN QASAKRGSLE TKDDIPFRKV LGNPGRGSIK TVAGSGIART IPSLTSTSTP 130 140 150 160 170 180 LRSGLLENRT EKRKRMISTG SELNEDYPKE NDSSSNNKAM TDPSRKYLTS SREKQLSLKQ 190 200 210 220 230 240 SEENRTSGLL PLQSSSFYGS RAGSKEHSSG GTNLDRTNVS SQTPSAKRSL GFLPQPVPLS 250 260 270 280 290 300 VKKLRCNQDY TGWNKPRVPL SSHQQQQLQG FSNLGNTCYM NAILQSLFSL QSFANDLLKQ 310 320 330 340 350 360 GIPWKKIPLN ALIRRFAHLL VKKDICNSET KKDLLKKVKN AISATAERFS GYMQNDAHEF 370 380 390 400 410 420 LSQCLDQLKE DMEKLNKTWK TEPVSGEENS PDISATRAYT CPVITNLEFE VQHSIICKAC 430 440 450 460 470 480 GEIIPKREQF NDLSIDLPRR KKPLPPRSIQ DSLDLFFRAE ELEYSCEKCG GKCALVRHKF 490 500 510 520 530 540 NRLPRVLILH LKRYSFNVAL SLNNKIGQQV IIPRYLTLSS HCTENTKPPF TLGWSAHMAM 550 560 570 580 590 600 KFTFKSKSSL ALCLDSDSED ELKRSVALSQ RLCEMLGNEQ QQEDLEKDSK LCPIEPDKSE 610 620 630 640 650 660 LENSGFDRMS EEELLAAVLE ISKRDASPSL SHEDDDKPTS SPDTGFAEDD IQEMPENPDT 670 680 690 700 710 720 METEKPKTIT ELDPASFTEI TKDCDENKEN KTPEGSQGEV DWLQQYDMER EREEQELQQA 730 740 750 760 770 780 LAQSLQEQEA WEQKEDDDLK RATELSLQEF NNSFVDALGS DEDSGNEDVF DMEYTEAEAE 790 800 810 820 830 840 ELKRNAETGN LPHSYRLISV VSHIGSTSSS GHYISDVYDI KKQAWFTYND LEVSKIQEAA 850 860 870 880 VQSDRDRSGY IFFYMHKEIF DELLETEKNS QSLSTEVGKT TRQAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT SER-979. Tissue: Spinal cord.
[2]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT SER-979.
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), VARIANT SER-979. Tissue: Testis.
[5]	"Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro." Nagase T., Kikuno R., Nakayama M., Hirosawa M., Ohara O. DNA Res. 7:273-281(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 49-979 (ISOFORM 1), VARIANT SER-979. Tissue: Brain.
[6]	"Cloning and enzymatic analysis of 22 novel human ubiquitin-specific proteases." Quesada V., Diaz-Perales A., Gutierrez-Fernandez A., Garabaya C., Cal S., Lopez-Otin C. Biochem. Biophys. Res. Commun. 314:54-62(2004) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, ENZYME ACTIVITY.
[7]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-650 AND SER-652, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[8]	"Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry." Huang X., Summers M.K., Pham V., Lill J.R., Liu J., Lee G., Kirkpatrick D.S., Jackson P.K., Fang G., Dixit V.M. Mol. Cell 42:511-523(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, UBIQUITINATION, PHOSPHORYLATION AT SER-628 BY CDK2, DOMAIN KEN BOX 3, DEVELOPMENTAL STAGE, INDUCTION, INTERACTION WITH FZR1, MUTAGENESIS OF 32-LYS--ASN-34; 71-ARG-LEU-74; 96-ARG-LEU-99; 160-ARG-LEU-163; 221-LYS--ASN-223; CYS-350; 782-LYS--ASN-784 AND SER-628.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AL832645 mRNA. Translation: CAD89955.1.
BX538024 mRNA. Translation: CAD97970.1.
AC012510 Genomic DNA. No translation available.
AC073838 Genomic DNA. Translation: AAY14887.1. Sequence problems.
CH471063 Genomic DNA. Translation: EAW70621.1.
BC112901 mRNA. Translation: AAI12902.1.
BC133007 mRNA. Translation: AAI33008.1.
BC133009 mRNA. Translation: AAI33010.1.
BC144249 mRNA. Translation: AAI44250.1.
BC144252 mRNA. Translation: AAI44253.1.
AB046814 mRNA. Translation: BAB13420.1.

IPI

IPI00472977.
IPI00925754.

RefSeq

NP_065986.2. NM_020935.2.

UniGene

Hs.166068.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3U12	X-ray	2.08	A/B	4-125	[»]

ProteinModelPortal

Q86T82.

SMR

Q86T82. Positions 4-106, 337-598.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q86T82. 3 interactions.

STRING

9606.ENSP00000258399.

Protein family/group databases

MEROPS

C19.053.

PTM databases

PhosphoSite

Q86T82.

Polymorphism databases

DMDM

300669620.

Proteomic databases

PaxDb

Q86T82.

PRIDE

Q86T82.

Protocols and materials databases

DNASU

57695.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000258399; ENSP00000258399; ENSG00000135913.
ENST00000415516; ENSP00000400902; ENSG00000135913.
ENST00000418019; ENSP00000396585; ENSG00000135913.
ENST00000454775; ENSP00000393662; ENSG00000135913.

GeneID

57695.

KEGG

hsa:57695.

UCSC

uc002vie.2. human.
uc002vig.2. human.

Organism-specific databases

CTD

57695.

GeneCards

GC02M219281.

HGNC

HGNC:20063. USP37.

HPA

HPA045160.

neXtProt

NX_Q86T82.

PharmGKB

PA134928706.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5207.

HOVERGEN

HBG055893.

InParanoid

Q86T82.

KO

K11850.

OMA

LQEFNNS.

OrthoDB

EOG4S4PFQ.

PhylomeDB

Q86T82.

Gene expression databases

ArrayExpress

Q86T82.

Bgee

Q86T82.

CleanEx

HS_USP37.

Genevestigator

Q86T82.

GermOnline

ENSG00000135913. Homo sapiens.

Family and domain databases

InterPro

IPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19.
IPR003903. Ubiquitin-int_motif.
[Graphical view]

Pfam

PF00443. UCH. 1 hit.
PF02809. UIM. 3 hits.
[Graphical view]

SMART

SM00726. UIM. 4 hits.
[Graphical view]

PROSITE

PS00972. UCH_2_1. 1 hit.
PS00973. UCH_2_2. 1 hit.
PS50235. UCH_2_3. 1 hit.
PS50330. UIM. 3 hits.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

USP37. human.

GenomeRNAi

57695.

NextBio

64543.

Entry information

Entry name

UBP37_HUMAN

Accession

Primary (citable) accession number: Q86T82
Secondary accession number(s): A2RUQ8 , B7ZM38, B7ZM41, E9PHL3, Q2KHT2, Q53S10, Q7Z3A5, Q9HCH8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 10, 2003
Last sequence update:	July 13, 2010
Last modified:	May 1, 2013
This is version 90 of the entry and version 2 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.