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Protein

Parafibromin

Gene

CDC73

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways. May be involved in cell cycle progression through the regulation of cyclin D1/PRAD1 expression. Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both indepentently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Connects PAF1C with the cleavage and polyadenylation specificity factor (CPSF) complex and the cleavage stimulation factor (CSTF) complex, and with Wnt signaling. Involved in polyadenylation of mRNA precursors.10 Publications

GO - Molecular functioni

GO - Biological processi

  • beta-catenin-TCF complex assembly Source: Reactome
  • cell cycle Source: UniProtKB-KW
  • cellular response to lipopolysaccharide Source: UniProtKB
  • endodermal cell fate commitment Source: UniProtKB
  • histone H2B ubiquitination Source: UniProtKB
  • histone monoubiquitination Source: UniProtKB
  • mRNA polyadenylation Source: UniProtKB
  • negative regulation of apoptotic process Source: Ensembl
  • negative regulation of cell proliferation Source: UniProtKB
  • negative regulation of epithelial cell proliferation Source: UniProtKB
  • negative regulation of fibroblast proliferation Source: UniProtKB
  • negative regulation of G1/S transition of mitotic cell cycle Source: UniProtKB
  • negative regulation of myeloid cell differentiation Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of mRNA 3'-end processing Source: UniProtKB
  • positive regulation of transcription elongation from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of Wnt signaling pathway Source: UniProtKB
  • protein destabilization Source: UniProtKB
  • protein ubiquitination Source: Reactome
  • recruitment of 3'-end processing factors to RNA polymerase II holoenzyme complex Source: GO_Central
  • regulation of cell growth Source: Ensembl
  • stem cell population maintenance Source: UniProtKB
  • transcription elongation from RNA polymerase II promoter Source: Reactome
  • transcription from RNA polymerase II promoter Source: Reactome
  • Wnt signaling pathway Source: UniProtKB-KW

Keywordsi

Biological processCell cycle, Transcription, Transcription regulation, Wnt signaling pathway

Enzyme and pathway databases

ReactomeiR-HSA-112382. Formation of RNA Pol II elongation complex.
R-HSA-112387. Elongation arrest and recovery.
R-HSA-201722. Formation of the beta-catenin:TCF transactivating complex.
R-HSA-5632684. Hedgehog 'on' state.
R-HSA-674695. RNA Polymerase II Pre-transcription Events.
R-HSA-75955. RNA Polymerase II Transcription Elongation.
R-HSA-8866654. E3 ubiquitin ligases ubiquitinate target proteins.
SignaLinkiQ6P1J9.
SIGNORiQ6P1J9.

Names & Taxonomyi

Protein namesi
Recommended name:
Parafibromin
Alternative name(s):
Cell division cycle protein 73 homolog
Hyperparathyroidism 2 protein
Gene namesi
Name:CDC73
Synonyms:C1orf28, HRPT2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:16783. CDC73.

Subcellular locationi

GO - Cellular componenti

  • Cdc73/Paf1 complex Source: UniProtKB
  • cytosol Source: HPA
  • nuclear chromosome, telomeric region Source: BHF-UCL
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Hyperparathyroidism 1 (HRPT1)5 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant disorder characterized by hypercalcemia, elevated parathyroid hormone (PTH) levels, and uniglandular or multiglandular parathyroid hyperplasia, adenomas, and carcinomas.
See also OMIM:145000
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06493163L → P in HRPT1; unknown pathological significance. 1 Publication1
Natural variantiVAR_02408264L → P in HRPT1; does not affect interaction with the Pfa1 complex. 3 PublicationsCorresponds to variant dbSNP:rs121434264Ensembl.1
Natural variantiVAR_06493395L → P in HRPT1; unknown pathological significance; found as somatic mutation in a parathyroid adenoma sample from a patient who also carries a germline frameshift mutation. 1 Publication1
Hyperparathyroidism 2 with jaw tumors (HRPT2)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant neoplasia syndrome characterized by primary hyperparathyroidism, ossifying fibroma of the maxilla and/or mandible, renal tumor, and uterine tumors. It is associated with increased risk of parathyroid cancer.
See also OMIM:145001
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0649285 – 10Missing in HRPT2; unknown pathological significance; found as somatic mutation in a parathyroid carcinoma sample from a patient who also carries a germline mutation causing a splicing defect. 1 Publication6
Natural variantiVAR_064936379D → N in HRPT2. 1 Publication1
Parathyroid carcinoma (PRTC)1 Publication
The gene represented in this entry is involved in disease pathogenesis.
Disease descriptionThese cancers characteristically result in more profound clinical manifestations of hyperparathyroidism than do parathyroid adenomas, the most frequent cause of primary hyperparathyroidism. Early en bloc resection of the primary tumor is the only curative treatment.
See also OMIM:608266

Keywords - Diseasei

Disease mutation, Tumor suppressor

Organism-specific databases

DisGeNETi79577.
MalaCardsiCDC73.
MIMi145000. phenotype.
145001. phenotype.
608266. phenotype.
OpenTargetsiENSG00000134371.
Orphaneti99879. Familial isolated hyperparathyroidism.
99877. Familial parathyroid adenoma.
99880. Hyperparathyroidism-jaw tumor syndrome.
143. Parathyroid carcinoma.
PharmGKBiPA29464.

Polymorphism and mutation databases

BioMutaiCDC73.
DMDMi74749063.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources1 Publication
ChainiPRO_00001918032 – 531ParafibrominAdd BLAST530

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1 Publication1
Modified residuei212PhosphoserineCombined sources1
Cross-linki301Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources

Post-translational modificationi

Phosphorylated. Dephosphorylated by PTPN11.1 Publication

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ6P1J9.
MaxQBiQ6P1J9.
PaxDbiQ6P1J9.
PeptideAtlasiQ6P1J9.
PRIDEiQ6P1J9.

PTM databases

iPTMnetiQ6P1J9.
PhosphoSitePlusiQ6P1J9.

Expressioni

Tissue specificityi

Found in adrenal and parathyroid glands, kidney and heart.1 Publication

Gene expression databases

BgeeiENSG00000134371.
CleanExiHS_CDC73.
ExpressionAtlasiQ6P1J9. baseline and differential.
GenevisibleiQ6P1J9. HS.

Organism-specific databases

HPAiCAB016359.
HPA030772.

Interactioni

Subunit structurei

Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and WDR61. Interacts with POLR2A, CPSF1, CPSF4, CSTF2, KMT2A/MLL1 and CTNNB1. Interacts with a Set1-like complex that has histone methyltransferase activity and methylates histone H3. Found in a complex with BCL9L or BCL9, CDC73, CTNNB1 and PYGO1 indicative for the participation in a nuclear Wnt signaling complex. Interacts with PTPN11 (PubMed:26742426).9 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • RNA polymerase II core binding Source: UniProtKB

Protein-protein interaction databases

BioGridi122724. 247 interactors.
DIPiDIP-37884N.
IntActiQ6P1J9. 80 interactors.
MINTiMINT-2817439.
STRINGi9606.ENSP00000356405.

Structurei

3D structure databases

ProteinModelPortaliQ6P1J9.
SMRiQ6P1J9.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni200 – 531Interaction with POLR2A and PAF1Add BLAST332
Regioni200 – 250Interaction with CTNNB11 PublicationAdd BLAST51

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi125 – 139Nuclear localization signalAdd BLAST15

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi361 – 364Poly-Ile4

Sequence similaritiesi

Belongs to the CDC73 family.Curated

Phylogenomic databases

eggNOGiKOG3786. Eukaryota.
COG5157. LUCA.
GeneTreeiENSGT00390000001114.
HOVERGENiHBG055033.
InParanoidiQ6P1J9.
KOiK15175.
OMAiKKLQGCQ.
OrthoDBiEOG091G0A8X.
PhylomeDBiQ6P1J9.
TreeFamiTF313016.

Family and domain databases

InterProiView protein in InterPro
IPR007852. Cdc73/Parafibromin.
IPR031336. CDC73_C.
IPR032041. Cdc73_N.
PANTHERiPTHR12466. PTHR12466. 1 hit.
PfamiView protein in Pfam
PF05179. CDC73_C. 1 hit.
PF16050. CDC73_N. 1 hit.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q6P1J9-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MADVLSVLRQ YNIQKKEIVV KGDEVIFGEF SWPKNVKTNY VVWGTGKEGQ
60 70 80 90 100
PREYYTLDSI LFLLNNVHLS HPVYVRRAAT ENIPVVRRPD RKDLLGYLNG
110 120 130 140 150
EASTSASIDR SAPLEIGLQR STQVKRAADE VLAEAKKPRI EDEECVRLDK
160 170 180 190 200
ERLAARLEGH KEGIVQTEQI RSLSEAMSVE KIAAIKAKIM AKKRSTIKTD
210 220 230 240 250
LDDDITALKQ RSFVDAEVDV TRDIVSRERV WRTRTTILQS TGKNFSKNIF
260 270 280 290 300
AILQSVKARE EGRAPEQRPA PNAAPVDPTL RTKQPIPAAY NRYDQERFKG
310 320 330 340 350
KEETEGFKID TMGTYHGMTL KSVTEGASAR KTQTPAAQPV PRPVSQARPP
360 370 380 390 400
PNQKKGSRTP IIIIPAATTS LITMLNAKDL LQDLKFVPSD EKKKQGCQRE
410 420 430 440 450
NETLIQRRKD QMQPGGTAIS VTVPYRVVDQ PLKLMPQDWD RVVAVFVQGP
460 470 480 490 500
AWQFKGWPWL LPDGSPVDIF AKIKAFHLKY DEVRLDPNVQ KWDVTVLELS
510 520 530
YHKRHLDRPV FLRFWETLDR YMVKHKSHLR F
Length:531
Mass (Da):60,577
Last modified:July 5, 2004 - v1
Checksum:i894A7448DBC0E793
GO

Sequence cautioni

The sequence AAH07325 differs from that shown. Contaminating sequence. Potential poly-A sequence starting in position 300.Curated
The sequence BAB15608 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti123Q → G in AAH14351 (PubMed:15489334).Curated1
Sequence conflicti184 – 187AIKA → CNQT in BAB15608 (PubMed:14702039).Curated4
Sequence conflicti372I → K in BAB15608 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0649272A → S Found in parathyroid adenoma samples; somatic mutation; parathyroid adenoma samples are from a patient with isolated hyperparathyroidism who also carries germline mutation P-91. 1 Publication1
Natural variantiVAR_0649285 – 10Missing in HRPT2; unknown pathological significance; found as somatic mutation in a parathyroid carcinoma sample from a patient who also carries a germline mutation causing a splicing defect. 1 Publication6
Natural variantiVAR_06492934K → Q Found in a clear cell renal carcinoma sample; somatic mutation; unlike wild-type protein the mutant is defective in suppressing CCND1 expression in vivo. 1 Publication1
Natural variantiVAR_06493059S → F Found in a parathyroid carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_06493163L → P in HRPT1; unknown pathological significance. 1 Publication1
Natural variantiVAR_02408264L → P in HRPT1; does not affect interaction with the Pfa1 complex. 3 PublicationsCorresponds to variant dbSNP:rs121434264Ensembl.1
Natural variantiVAR_06493291R → P Found in a patient with isolated hyperparathyroidism and parathyroid adenomas. 1 Publication1
Natural variantiVAR_06493395L → P in HRPT1; unknown pathological significance; found as somatic mutation in a parathyroid adenoma sample from a patient who also carries a germline frameshift mutation. 1 Publication1
Natural variantiVAR_064934272N → S Found in a parathyroid adenoma sample. 1 PublicationCorresponds to variant dbSNP:rs752383339Ensembl.1
Natural variantiVAR_064935292R → K Found in a Wilms tumor sample; somatic mutation. 1 Publication1
Natural variantiVAR_064936379D → N in HRPT2. 1 Publication1
Natural variantiVAR_031825384L → P. Corresponds to variant dbSNP:rs35590728Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF312865 mRNA. Translation: AAG45339.1.
AK026969 mRNA. Translation: BAB15608.1. Different initiation.
AK314772 mRNA. Translation: BAG37309.1.
AL139133, AL390863 Genomic DNA. Translation: CAH71049.1.
AL390863, AL139133 Genomic DNA. Translation: CAH71589.1.
CH471067 Genomic DNA. Translation: EAW91250.1.
BC007325 mRNA. Translation: AAH07325.1. Sequence problems.
BC014351 mRNA. Translation: AAH14351.2.
BC065037 mRNA. Translation: AAH65037.1.
CCDSiCCDS1382.1.
RefSeqiNP_078805.3. NM_024529.4.
UniGeneiHs.378996.

Genome annotation databases

EnsembliENST00000367435; ENSP00000356405; ENSG00000134371.
GeneIDi79577.
KEGGihsa:79577.
UCSCiuc001gtb.4. human.

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiCDC73_HUMAN
AccessioniPrimary (citable) accession number: Q6P1J9
Secondary accession number(s): A6NLZ8
, B2RBR2, Q6PK51, Q96A07, Q9H245, Q9H5L7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 20, 2005
Last sequence update: July 5, 2004
Last modified: June 7, 2017
This is version 144 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families