Q9UKF6 (CPSF3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cleavage and polyadenylation specificity factor subunit 3
EC=3.1.27.-

Alternative name(s):
Cleavage and polyadenylation specificity factor 73 kDa subunit
Short name=CPSF 73 kDa subunit
mRNA 3'-end-processing endonuclease CPSF-73

Gene names

Name:	CPSF3
Synonyms:	CPSF73

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

General annotation (Comments)

Function	Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Has endonuclease activity, and functions as mRNA 3'-end-processing endonuclease. Also involved in the histone 3'-end pre-mRNA processing. U7 snRNP-dependent protein that induces both the 3'-endoribonucleolytic cleavage of histone pre-mRNAs and acts as a 5' to 3' exonuclease for degrading the subsequent downstream cleavage product (DCP) of mature histone mRNAs. Cleavage occurs after the 5'-ACCCA-3' sequence in the histone pre-mRNA leaving a 3'hydroxyl group on the upstream fragment containing the stem loop (SL) and 5' phosphate on the downstream cleavage product (DCP) starting with CU nucleotides. The U7-dependent 5' to 3' exonuclease activity is processive and degrades the DCP RNA substrate even after complete removal of the U7-binding site. Binds to the downstream cleavage product (DCP) of histone pre-mRNAs and the cleaved DCP RNA substrate in a U7 snRNP dependent manner. Ref.6 Ref.7 Ref.9 Ref.14
Cofactor	Binds 2 zinc ions per subunit.
Subunit structure	Component of the cleavage and polyadenylation specificity factor (CPSF) complex, composed of CPSF1, CPSF2, CPSF3, CPSF4 and FIP1L1. Interacts with CPSF2, CSTF2 and SYMPK. Interacts with TUT1; the interaction is direct and mediates the recruitment of the CPSF complex on the 3'UTR of pre-mRNAs. Interacts with WDR33. Ref.6 Ref.9 Ref.10 Ref.11
Subcellular location	Nucleus Ref.7.
Post-translational modification	Sumoylated on Lys-462, Lys-465 and Lys-545, preferentially by SUMO3. Ref.8
Sequence similarities	Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. CPSF3 subfamily.

Ontologies

Keywords
Biological process	mRNA processing
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Ligand	Metal-binding RNA-binding Zinc
Molecular function	Endonuclease Hydrolase Nuclease Ribonucleoprotein
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	histone mRNA 3'-end processing Inferred from direct assay Ref.9. Source: UniProtKB mRNA cleavage Traceable author statement PubMed 8929409. Source: ProtInc mRNA export from nucleus Traceable author statement. Source: Reactome mRNA polyadenylation Traceable author statement PubMed 8929409. Source: ProtInc mRNA splicing, via spliceosome Traceable author statement. Source: Reactome termination of RNA polymerase II transcription Traceable author statement. Source: Reactome
Cellular_component	mRNA cleavage and polyadenylation specificity factor complex Inferred from direct assay PubMed 18305108Ref.11. Source: UniProtKB ribonucleoprotein complex Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	5'-3' exonuclease activity Inferred from sequence or structural similarity. Source: UniProtKB RNA binding Inferred from sequence or structural similarity. Source: UniProtKB endoribonuclease activity Inferred from sequence or structural similarity. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 684

684

Cleavage and polyadenylation specificity factor subunit 3

PRO_0000074400

Sites

Active site

396

1

Proton donor Potential

Metal binding

71

1

Zinc 1

Metal binding

73

1

Zinc 1

Metal binding

75

1

Zinc 2

Metal binding

76

1

Zinc 2

Metal binding

158

1

Zinc 1

Metal binding

179

1

Zinc 1

Metal binding

179

1

Zinc 2

Metal binding

418

1

Zinc 2

Amino acid modifications

Modified residue

681

1

Phosphothreonine Ref.12

Cross-link

462

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.8

Cross-link

465

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.8

Cross-link

545

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.8

Natural variations

Natural variant

142

1

E → G. Ref.4
Corresponds to variant rs17850770 [ dbSNP | Ensembl ].

VAR_037646

Natural variant

578

1

D → N in a breast cancer sample; somatic mutation. Ref.15

VAR_035873

Experimental info

Mutagenesis

73

1

H → A: Inhibits histone 3'-end processing. Ref.9 Ref.14

Mutagenesis

75 – 76

2

DH → KA: Loss of histone 3'-end processing. Ref.9 Ref.14

Mutagenesis

75

1

D → A: Inhibits histone 3'-end processing. Ref.9 Ref.14

Mutagenesis

76

1

H → A: Inhibits histone 3'-end processing. Ref.9 Ref.14

Mutagenesis

334

1

S → A: Does not inhibit histone 3'-end processing. Ref.9 Ref.14

Mutagenesis

396

1

H → A: Inhibits histone 3'-end processing. Ref.9 Ref.14

Mutagenesis

462

1

K → R: Reduced sumoylation; when associated with R-465 and R-545. Ref.8 Ref.14

Mutagenesis

465

1

K → R: Reduced sumoylation; when associated with R-462 and R-545. Ref.8 Ref.14

Mutagenesis

545

1

K → R: Reduced sumoylation; when associated with R-462 and R-465. Ref.8 Ref.14

Secondary structure

1

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684

Helix Strand Turn

Details...

Beta strand

10 – 25

16

Beta strand

27 – 32

6

Beta strand

35 – 39

5

Helix

49 – 52

4

Helix

56 – 58

3

Helix

61 – 63

3

Beta strand

66 – 68

3

Helix

74 – 77

4

Helix

80 – 86

7

Beta strand

91 – 96

6

Helix

97 – 110

14

Helix

125 – 131

7

Helix

132 – 134

3

Beta strand

135 – 138

4

Beta strand

144 – 146

3

Beta strand

149 – 155

7

Beta strand

163 – 169

7

Beta strand

172 – 176

5

Beta strand

186 – 188

3

Beta strand

199 – 204

6

Turn

206 – 209

4

Helix

215 – 231

17

Beta strand

235 – 239

5

Beta strand

242 – 245

4

Helix

246 – 259

14

Helix

261 – 263

3

Beta strand

268 – 271

4

Helix

275 – 284

10

Turn

285 – 287

3

Beta strand

307 – 310

4

Helix

314 – 316

3

Beta strand

321 – 328

8

Helix

335 – 344

10

Beta strand

351 – 354

4

Helix

363 – 367

5

Beta strand

372 – 375

4

Beta strand

381 – 383

3

Beta strand

386 – 390

5

Helix

399 – 409

11

Beta strand

412 – 419

8

Helix

421 – 435

15

Beta strand

444 – 446

3

Beta strand

454 – 458

5

Sequences

	Sequence		Length	Mass (Da)
	Q9UKF6 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: F8AA24EA6FB78377	FASTA	684	77,486
	10 20 30 40 50 60 MSAIPAEESD QLLIRPLGAG QEVGRSCIIL EFKGRKIMLD CGIHPGLEGM DALPYIDLID 70 80 90 100 110 120 PAEIDLLLIS HFHLDHCGAL PWFLQKTSFK GRTFMTHATK AIYRWLLSDY VKVSNISADD 130 140 150 160 170 180 MLYTETDLEE SMDKIETINF HEVKEVAGIK FWCYHAGHVL GAAMFMIEIA GVKLLYTGDF 190 200 210 220 230 240 SRQEDRHLMA AEIPNIKPDI LIIESTYGTH IHEKREEREA RFCNTVHDIV NRGGRGLIPV 250 260 270 280 290 300 FALGRAQELL LILDEYWQNH PELHDIPIYY ASSLAKKCMA VYQTYVNAMN DKIRKQININ 310 320 330 340 350 360 NPFVFKHISN LKSMDHFDDI GPSVVMASPG MMQSGLSREL FESWCTDKRN GVIIAGYCVE 370 380 390 400 410 420 GTLAKHIMSE PEEITTMSGQ KLPLKMSVDY ISFSAHTDYQ QTSEFIRALK PPHVILVHGE 430 440 450 460 470 480 QNEMARLKAA LIREYEDNDE VHIEVHNPRN TEAVTLNFRG EKLAKVMGFL ADKKPEQGQR 490 500 510 520 530 540 VSGILVKRNF NYHILSPCDL SNYTDLAMST VKQTQAIPYT GPFNLLCYQL QKLTGDVEEL 550 560 570 580 590 600 EIQEKPALKV FKNITVIQEP GMVVLEWLAN PSNDMYADTV TTVILEVQSN PKIRKGAVQK 610 620 630 640 650 660 VSKKLEMHVY SKRLEIMLQD IFGEDCVSVK DDSILSVTVD GKTANLNLET RTVECEEGSE 670 680 DDESLREMVE LAAQRLYEAL TPVH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Homo sapiens mRNA for CPSF (cleavage and polyadenylation specificity factor) 73 kDa subunit." Yu S., Chen W., Pang X., Dong X., Wang H. Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Hepatoma.
[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].
[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], VARIANT GLY-142. Tissue: Brain and Uterus.
[5]	"H. sapiens mRNA for the 73 kDa subunit of CPSF (cleavage and polyadenylation specificity factor, partial cds)." Pusch W. Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 120-498.
[6]	"Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase." Kaufmann I., Martin G., Friedlein A., Langen H., Keller W. EMBO J. 23:616-626(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PRE-MRNA 3'-END PROCESSING, IDENTIFICATION IN THE CPSF COMPLEX.
[7]	"Evidence that polyadenylation factor CPSF-73 is the mRNA 3' processing endonuclease." Ryan K., Calvo O., Manley J.L. RNA 10:565-573(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[8]	"Sumoylation modulates the assembly and activity of the pre-mRNA 3' processing complex." Vethantham V., Rao N., Manley J.L. Mol. Cell. Biol. 27:8848-8858(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUMOYLATION AT LYS-462; LYS-465 AND LYS-545, MUTAGENESIS OF LYS-462; LYS-465 AND LYS-545.
[9]	"Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3'-end maturation." Kolev N.G., Yario T.A., Benson E., Steitz J.A. EMBO Rep. 9:1013-1018(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH CPSF2; CSTF2 AND SYMPK, MUTAGENESIS OF HIS-73; ASP-75; HIS-76; SER-334 AND HIS-396.
[10]	"Molecular architecture of the human pre-mRNA 3' processing complex." Shi Y., Di Giammartino D.C., Taylor D., Sarkeshik A., Rice W.J., Yates J.R. III, Frank J., Manley J.L. Mol. Cell 33:365-376(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH WDR33.
[11]	"The poly A polymerase Star-PAP controls 3'-end cleavage by promoting CPSF interaction and specificity toward the pre-mRNA." Laishram R.S., Anderson R.A. EMBO J. 29:4132-4145(2010) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN THE CPSF COMPLEX, INTERACTION WITH TUT1.
[12]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-681, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]	"Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease." Mandel C.R., Kaneko S., Zhang H., Gebauer D., Vethantham V., Manley J.L., Tong L. Nature 444:953-956(2006) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1-459 IN COMPLEX WITH ZINC IONS, FUNCTION, MUTAGENESIS OF 75-ASP-HIS-76.
[15]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] ASN-578.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF171877 mRNA. Translation: AAF00224.1.
AC080162 Genomic DNA. Translation: AAY14858.1.
CH471053 Genomic DNA. Translation: EAX00989.1.
BC011654 mRNA. Translation: AAH11654.1.
BC020211 mRNA. Translation: AAH20211.1.
AF017269 mRNA. Translation: AAB70268.1.

IPI

IPI00007818.

RefSeq

NP_057291.1. NM_016207.3.

UniGene

Hs.515972.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2I7T	X-ray	2.10	A	1-459	[»]
2I7V	X-ray	2.10	A	1-459	[»]

ProteinModelPortal

Q9UKF6.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-42501N.

MINT

MINT-1742891.

STRING

9606.ENSP00000238112.

PTM databases

PhosphoSite

Q9UKF6.

Polymorphism databases

DMDM

18203503.

Proteomic databases

PaxDb

Q9UKF6.

PeptideAtlas

Q9UKF6.

PRIDE

Q9UKF6.

Protocols and materials databases

DNASU

51692.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000238112; ENSP00000238112; ENSG00000119203.

GeneID

51692.

KEGG

hsa:51692.

UCSC

uc002qzo.1. human.

Organism-specific databases

CTD

51692.

GeneCards

GC02P009514.

HGNC

HGNC:2326. CPSF3.

HPA

HPA034657.

MIM

606029. gene.

neXtProt

NX_Q9UKF6.

PharmGKB

PA26843.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1236.

HOGENOM

HOG000203394.

HOVERGEN

HBG051107.

InParanoid

Q9UKF6.

KO

K14403.

OMA

YVSFSAH.

OrthoDB

EOG4FN4H6.

PhylomeDB

Q9UKF6.

Enzyme and pathway databases

Reactome

REACT_1675. mRNA Processing.
REACT_1788. Transcription.
REACT_71. Gene Expression.
REACT_78. Post-Elongation Processing of the Transcript.

Gene expression databases

ArrayExpress

Q9UKF6.

Bgee

Q9UKF6.

CleanEx

HS_CPSF3.

Genevestigator

Q9UKF6.

GermOnline

ENSG00000119203. Homo sapiens.

Family and domain databases

InterPro

IPR001279. Beta-lactamas-like.
IPR022712. Beta_Casp.
IPR021718. CPSF73-100_C.
IPR011108. RMMBL.
[Graphical view]

Pfam

PF10996. Beta-Casp. 1 hit.
PF11718. CPSF73-100_C. 1 hit.
PF00753. Lactamase_B. 1 hit.
PF07521. RMMBL. 1 hit.
[Graphical view]

SMART

SM01027. Beta-Casp. 1 hit.
SM01098. CPSF73-100_C. 1 hit.
SM00849. Lactamase_B. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

CPSF3. human.

EvolutionaryTrace

Q9UKF6.

GenomeRNAi

51692.

NextBio

55702.

SOURCE

Search...

Entry information

Entry name

CPSF3_HUMAN

Accession

Primary (citable) accession number: Q9UKF6
Secondary accession number(s): O14769, Q53RS2, Q96F36

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 18, 2001
Last sequence update:	May 1, 2000
Last modified:	May 1, 2013
This is version 104 of the entry and version 1 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.