O43809 (CPSF5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cleavage and polyadenylation specificity factor subunit 5

Alternative name(s):
Cleavage and polyadenylation specificity factor 25 kDa subunit
Short name=CFIm25
Short name=CPSF 25 kDa subunit
Nucleoside diphosphate-linked moiety X motif 21
Short name=Nudix motif 21
Pre-mRNA cleavage factor Im 25 kDa subunit

Gene names

Name:	NUDT21
Synonyms:	CFIM25, CPSF25, CPSF5

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	227 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	Component of the cleavage factor Im (CFIm) complex that plays a key role in pre-mRNA 3'-processing. Involved in association with CPSF6 or CPSF7 in pre-MRNA 3'-end poly(A) site cleavage and poly(A) addition. NUDT21/CPSF5 binds to cleavage and polyadenylation RNA substrates. The homodimer mediates simultaneous sequence-specific recognition of two 5'-UGUA-3' elements within the pre-mRNA. Binds to, but does not hydrolyze mono- and di-adenosine nucleotides. May have a role in mRNA export. Ref.1 Ref.7 Ref.8 Ref.14 Ref.18 Ref.20
Subunit structure	Homodimer. Component of the cleavage factor Im (CFIm) complex, composed of, at least, NUDT21/CPSF5 and CPSF6 or CPSF7. Within the cleavage factor Im complex, the NUDT21/CPSF5 homodimer is at the core of a heterotetramer, and is clasped by two additional subunits (CPSF6 or CPSF7). Interacts with CPSF6, CPSF7, PABPN1 and SNRNP70. Interacts with PAPOLA; the interaction is diminished by acetylation. Ref.1 Ref.7 Ref.9 Ref.10 Ref.12 Ref.14 Ref.16 Ref.18 Ref.19 Ref.20
Subcellular location	Nucleus. Note: In punctate subnuclear structures localized adjacent to nuclear speckles, called paraspeckles. Ref.1 Ref.10 Ref.14
Post-translational modification	Acetylated mainly by p300/CBP, recruited to the complex by CPSF6. Acetylation decreases interaction with PAPAO. Deacetylated by the class I/II HDACs, HDAC1, HDAC3 and HDAC10, and by the class III HDACs, SIRT1 AND SIRT2.
Sequence similarities	Belongs to the Nudix hydrolase family. CPSF5 subfamily. Contains 1 nudix hydrolase domain.
Caution	Lacks the conserved metal-binding residues in the NUDIX motif and does not have hydrolase activity.

Ontologies

Keywords
Biological process	mRNA processing
Cellular component	Nucleus
Ligand	RNA-binding
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	mRNA polyadenylation Inferred from mutant phenotype Ref.14. Source: UniProtKB mRNA splicing, via spliceosome Traceable author statement. Source: Reactome protein tetramerization Inferred from direct assay Ref.20. Source: UniProtKB termination of RNA polymerase II transcription Traceable author statement. Source: Reactome
Cellular_component	centrosome Inferred from direct assay. Source: LIFEdb mRNA cleavage factor complex Inferred from direct assay Ref.14Ref.20. Source: UniProtKB paraspeckles Inferred from direct assay Ref.10. Source: UniProtKB
Molecular_function	AU-rich element binding Inferred from direct assay Ref.18Ref.20. Source: UniProtKB hydrolase activity Inferred from electronic annotation. Source: InterPro mRNA binding Inferred from direct assay Ref.20. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATXN1	P54253	2	EBI-355720,EBI-930964

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.6

Chain

2 – 227

226

Cleavage and polyadenylation specificity factor subunit 5

PRO_0000057150

Regions

Domain

76 – 201

126

Nudix hydrolase

Region

2 – 147

146

Necessary for RNA-binding

Region

81 – 160

80

Necessary for interactions with PAPOLA and PABPN1

Region

102 – 104

3

Interaction with RNA

Motif

109 – 130

22

Nudix box

Sites

Site

55

1

Interaction with RNA

Site

63

1

Interaction with RNA

Site

208

1

Interaction with RNA

Amino acid modifications

Modified residue

2

1

N-acetylserine Ref.6

Modified residue

23

1

N6-acetyllysine Ref.12 Ref.13

Modified residue

29

1

N6-acetyllysine Ref.13

Modified residue

40

1

Phosphotyrosine Ref.11

Modified residue

56

1

N6-acetyllysine Ref.13

Experimental info

Mutagenesis

23

1

K → R: Abolishes acetylation. Ref.12

Mutagenesis

29

1

K → R: No effect on acetylation. Ref.12

Mutagenesis

55

1

E → A: Reduces affinity for UGUA RNA by 88%. Ref.18 Ref.20

Mutagenesis

63

1

R → S: Reduces affinity for UGUA RNA by 99%. Ref.18 Ref.20

Mutagenesis

81

1

E → A: Reduces affinity for UGUA RNA by 12%. Ref.18

Mutagenesis

103

1

F → A: Reduces affinity for UGUA RNA by 99%. Ref.18 Ref.20

Mutagenesis

103

1

F → W: Reduces affinity for UGUA RNA by over 90%. Ref.18 Ref.20

Mutagenesis

154

1

E → A: Reduces affinity for UGUA RNA by 50%.

Mutagenesis

158

1

Y → A: Abolishes interaction with CPSF6; when associated with A-160. Ref.20

Mutagenesis

160

1

Y → A: Abolishes interaction with CPSF6; when associated with A-158. Ref.20

Sequence conflict

57

1

D → G in CAG33200. Ref.2

Sequence conflict

112

1

N → D in CAD97606. Ref.3

Sequence conflict

218

1

L → P in CAD97606. Ref.3

Secondary structure

1

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227

Helix Strand Turn

Details...

Turn

31 – 33

3

Beta strand

36 – 39

4

Helix

42 – 44

3

Beta strand

45 – 50

6

Helix

60 – 74

15

Beta strand

76 – 88

13

Beta strand

91 – 100

10

Beta strand

103 – 105

3

Beta strand

107 – 110

4

Helix

117 – 129

13

Beta strand

132 – 134

3

Beta strand

140 – 150

11

Beta strand

152 – 155

4

Beta strand

158 – 160

3

Beta strand

169 – 178

10

Beta strand

181 – 188

8

Beta strand

192 – 197

6

Helix

198 – 201

4

Helix

205 – 212

8

Helix

215 – 219

5

Beta strand

223 – 226

4

Sequences

	Sequence		Length	Mass (Da)
	O43809 [UniParc]. Last modified June 1, 1998. Version 1. Checksum: D204243E57F1CCC5	FASTA	227	26,227
	10 20 30 40 50 60 MSVVPPNRSQ TGWPRGVTQF GNKYIQQTKP LTLERTINLY PLTNYTFGTK EPLYEKDSSV 70 80 90 100 110 120 AARFQRMREE FDKIGMRRTV EGVLIVHEHR LPHVLLLQLG TTFFKLPGGE LNPGEDEVEG 130 140 150 160 170 180 LKRLMTEILG RQDGVLQDWV IDDCIGNWWR PNFEPPQYPY IPAHITKPKE HKKLFLVQLQ 190 200 210 220 EKALFAVPKN YKLVAAPLFE LYDNAPGYGP IISSLPQLLS RFNFIYN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human pre-mRNA cleavage factor Im is related to spliceosomal SR proteins and can be reconstituted in vitro from recombinant subunits." Rueegsegger U., Blank D., Keller W. Mol. Cell 1:243-253(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 60-73 AND 183-189, FUNCTION, IDENTIFICATION IN THE CLEAVAGE FACTOR IM COMPLEX, SUBCELLULAR LOCATION. Tissue: Brain.
[2]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"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]. Tissue: Retina.
[4]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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]. Tissue: Placenta.
[6]	Bienvenut W.V., Lilla S., von Kriegsheim A., Lempens A., Kolch W. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-15; 24-50 AND 79-131, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT SER-2, MASS SPECTROMETRY. Tissue: Ovarian carcinoma.
[7]	"Purification and characterization of human cleavage factor Im involved in the 3' end processing of messenger RNA precursors." Rueegsegger U., Beyer K., Keller W. J. Biol. Chem. 271:6107-6113(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, IDENTIFICATION IN A CLEAVAGE FACTOR IM COMPLEX, RNA-BINDING.
[8]	"A mechanism for the regulation of pre-mRNA 3' processing by human cleavage factor Im." Brown K.M., Gilmartin G.M. Mol. Cell 12:1467-1476(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, RNA-BINDING.
[9]	"Association of polyadenylation cleavage factor I with U1 snRNP." Awasthi S., Alwine J.C. RNA 9:1400-1409(2003) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A CLEAVAGE FACTOR IM COMPLEX, INTERACTION WITH CPSF6 AND SNRNP70, IDENTIFICATION BY MASS SPECTROMETRY.
[10]	"Distinct sequence motifs within the 68-kDa subunit of cleavage factor Im mediate RNA binding, protein-protein interactions, and subcellular localization." Dettwiler S., Aringhieri C., Cardinale S., Keller W., Barabino S.M. J. Biol. Chem. 279:35788-35797(2004) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A CLEAVAGE FACTOR IM COMPLEX, INTERACTION WITH CPSF6; PAPOLA AND PABPN1, RNA-BINDING, SUBCELLULAR LOCATION.
[11]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-40, MASS SPECTROMETRY.
[12]	"Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing." Shimazu T., Horinouchi S., Yoshida M. J. Biol. Chem. 282:4470-4478(2007) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION AT LYS-23, INTERACTION WITH PAPOLA AND CPSF6, MASS SPECTROMETRY, MUTAGENESIS OF LYS-23 AND LYS-29.
[13]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-23; LYS-29 AND LYS-56, MASS SPECTROMETRY.
[14]	"Evidence that cleavage factor Im is a heterotetrameric protein complex controlling alternative polyadenylation." Kim S., Yamamoto J., Chen Y., Aida M., Wada T., Handa H., Yamaguchi Y. Genes Cells 15:1003-1013(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBUNIT, SUBCELLULAR LOCATION.
[15]	"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].
[16]	"Crystal structure of the 25 kDa subunit of human cleavage factor Im." Coseno M., Martin G., Berger C., Gilmartin G., Keller W., Doublie S. Nucleic Acids Res. 36:3474-3483(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF APO FORM AND IN COMPLEX WITH BETA DIADENOSINE TETRAPHOSPHATE, LACK OF METAL-BINDING, HOMODIMERIZATION.
[17]	"The crystal structure of human cleavage and polyadenylation specific factor-5 reveals a dimeric Nudix protein with a conserved catalytic site." Tresaugues L., Stenmark P., Schaeler H., Flodin S., Welin M., Nyman T., Hammarstroem M., Moche M., Graeslund S., Nordlund P. Proteins 73:1047-1052(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF APO FORM AND IN COMPLEX WITH SULFATE.
[18]	"Structural basis of UGUA recognition by the Nudix protein CFI(m)25 and implications for a regulatory role in mRNA 3' processing." Yang Q., Gilmartin G.M., Doublie S. Proc. Natl. Acad. Sci. U.S.A. 107:10062-10067(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS) IN COMPLEXES WITH RNA UGUAAA AND UUGUAU, FUNCTION, SUBUNIT, MUTAGENESIS OF GLU-55; ARG-63; GLU-81 AND PHE-103.
[19]	"Crystal structure of the complex between the 25 kDA subunit and the 59 kDA subunit (RRM domain) of human cleavage factor Im." Structural genomics consortium (SGC) Submitted (JUL-2010) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.92 ANGSTROMS) OF 21-227 IN COMPLEX WITH CPSF7, SUBUNIT.
[20]	"Crystal structure of a human cleavage factor CFI(m)25/CFI(m)68/RNA complex provides an insight into poly(A) site recognition and RNA looping." Yang Q., Coseno M., Gilmartin G.M., Doublie S. Structure 19:368-377(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 21-227 IN COMPLEX WITH CPSF6 AND RNA, FUNCTION, SUBUNIT, MUTAGENESIS OF GLU-55; ARG-63; PHE-103; TYR-158 AND TYR-160.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AJ001810 mRNA. Translation: CAA05026.1.
CR456919 mRNA. Translation: CAG33200.1.
BX537360 mRNA. Translation: CAD97606.1.
AC092140 Genomic DNA. No translation available.
BC001403 mRNA. Translation: AAH01403.1.

IPI

IPI00646917.

RefSeq

NP_008937.1. NM_007006.2.

UniGene

Hs.528834.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2CL3	X-ray	1.90	A	21-227	[»]
2J8Q	X-ray	2.30	A/B	24-227	[»]
3BAP	X-ray	1.85	A	1-227	[»]
3BHO	X-ray	1.80	A	20-227	[»]
3MDG	X-ray	2.22	A/B	1-227	[»]
3MDI	X-ray	2.07	A/B	1-227	[»]
3N9U	X-ray	1.92	A/B	21-227	[»]
3P5T	X-ray	2.70	A/B/C/D/E/F	34-227	[»]
3P6Y	X-ray	2.90	A/B/E/F/I/J/M/N	34-227	[»]
3Q2S	X-ray	2.90	A/B	21-227	[»]
3Q2T	X-ray	3.06	A/B	21-227	[»]

ProteinModelPortal

O43809.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-42502N.

IntAct

O43809. 18 interactions.

MINT

MINT-5002263.

STRING

9606.ENSP00000300291.

PTM databases

PhosphoSite

O43809.

2D gel databases

UCD-2DPAGE

O43809.

Proteomic databases

PaxDb

O43809.

PeptideAtlas

O43809.

PRIDE

O43809.

Protocols and materials databases

DNASU

11051.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000300291; ENSP00000300291; ENSG00000167005.

GeneID

11051.

KEGG

hsa:11051.

UCSC

uc002eja.3. human.

Organism-specific databases

CTD

11051.

GeneCards

GC16M056463.

HGNC

HGNC:13870. NUDT21.

HPA

HPA019863.

MIM

604978. gene.

neXtProt

NX_O43809.

PharmGKB

PA26845.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG294795.

HOGENOM

HOG000161320.

HOVERGEN

HBG052968.

InParanoid

O43809.

KO

K14397.

OMA

ELNAGED.

OrthoDB

EOG4QVCCS.

PhylomeDB

O43809.

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

O43809.

Bgee

O43809.

CleanEx

HS_NUDT21.

Genevestigator

O43809.

GermOnline

ENSG00000167005. Homo sapiens.

Family and domain databases

Gene3D

3.90.79.10. 1 hit.

InterPro

IPR016706. Cleav_polyA_spec_factor_su5.
IPR000086. NUDIX_hydrolase_dom.
IPR015797. NUDIX_hydrolase_dom-like.
[Graphical view]

PANTHER

PTHR13047. PTHR13047. 1 hit.

Pfam

PF13869. NUDIX_2. 1 hit.
[Graphical view]

PIRSF

PIRSF017888. CPSF-25. 1 hit.

PROSITE

PS51462. NUDIX. 1 hit.
PS00893. NUDIX_BOX. False negative.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

NUDT21. human.

EvolutionaryTrace

O43809.

GenomeRNAi

11051.

NextBio

41991.

SOURCE

Search...

Entry information

Entry name

CPSF5_HUMAN

Accession

Primary (citable) accession number: O43809
Secondary accession number(s): Q6IB85, Q6NE84

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 7, 2006
Last sequence update:	June 1, 1998
Last modified:	May 1, 2013
This is version 116 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.