Q9H9Z2 (LN28A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein lin-28 homolog A
Short name=Lin-28A

Alternative name(s):
Zinc finger CCHC domain-containing protein 1

Gene names

Name:	LIN28A
Synonyms:	CSDD1, LIN28, ZCCHC1

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	209 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	Acts as a 'translational enhancer', driving specific mRNAs to polysomes and thus increasing the efficiency of protein synthesis. Its association with the translational machinery and target mRNAs results in an increased number of initiation events per molecule of mRNA and, indirectly, in stabilizing the mRNAs. Binds IGF2 mRNA, MYOD1 mRNA, ARBP/36B4 ribosomal protein mRNA and its own mRNA. Essential for skeletal muscle differentiation program through the translational up-regulation of IGF2 expression By similarity. Acts as a suppressor of microRNA (miRNA) biogenesis by specifically binding the precursor let-7 (pre-let-7), a miRNA precursor. Acts by binding pre-let-7 and recruiting ZCCHC11/TUT4 uridylyltransferase, leading to the terminal uridylation of pre-let-7. Uridylated pre-let-7 miRNAs fail to be processed by Dicer and undergo degradation. Degradation of pre-let-7 in embryonic stem (ES) cells contributes to the maintenance of ES cells. In contrast, LIN28A down-regulation in neural stem cells by miR-125, allows the processing of pre-let-7. Specifically recognizes the 5'-GGAG-3' motif in the terminal loop of pre-let-7. Also recognizes and binds non pre-let-7 pre-miRNAs that contain the 5'-GGAG-3' motif in the terminal loop, leading to their terminal uridylation and subsequent degradation. Ref.12 Ref.13
Subunit structure	Monomer. During skeletal muscle differentiation, associated with translation initiation complexes in the polysomal compartment. Directly interacts with EIF3S2. Interaction with NCL is RNA-dependent By similarity. Interacts with ZCCHC11/TUT4. Ref.13
Subcellular location	Cytoplasm. Nucleus › nucleolus. Note: Nucleolar localization observed in 10-15% of the nuclei in differentiated myotubes By similarity. Shuttles between the cytoplasm and the nucleus. Localizes to cytoplasmic processing bodies and stress granules. Ref.11 Ref.12
Tissue specificity	Expressed in embryonic stem cells (ES cells), placenta and testis. Ref.7 Ref.8 Ref.9
Developmental stage	Expressed in fetal liver. Expression decreases during differentiation of ES cells or upon induction of neuronal differentiation by retinoic acid. Ref.7 Ref.8 Ref.9
Induction	Can be negatively regulated by the interaction of microRNAs miR-125a and miR-125b with at least two miRNA responsive elements (miREs) in the 3'-UTR of this gene. These interactions may reduce both translation efficiency and mRNA abundance. Negatively regulated by retinoic acid. Ref.6 Ref.10
Domain	The CSD domain is required for function in muscle differentiation By similarity. The CCHC zinc fingers interact with the GGAG motif at the 3' end of let-7 miRNAs precursors, more generally they bind the 5'-NGNNG-3' consensus motif with micromolar affinity. The CSD domain recognizes the loop at the 5' end. The flexible linker allows accommodating variable sequences and lengths among let-7 family members.
Miscellaneous	Overexpressed in primary tumors (overall frequency approximately 15%), overexpression being linked to repression of let-7 family miRNAs and derepression of let-7 targets. Facilitates cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types.
Sequence similarities	Belongs to the lin-28 family. Contains 2 CCHC-type zinc fingers. Contains 1 CSD (cold-shock) domain.

Ontologies

Keywords
Biological process	RNA-mediated gene silencing
Cellular component	Cytoplasm Nucleus
Domain	Repeat Zinc-finger
Ligand	Metal-binding RNA-binding Zinc
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	RNA 3'-end processing Inferred from mutant phenotype Ref.12Ref.13. Source: UniProtKB germ cell development Inferred from electronic annotation. Source: Compara miRNA catabolic process Inferred from mutant phenotype Ref.12Ref.13. Source: UniProtKB negative regulation of glial cell differentiation Inferred from electronic annotation. Source: Compara positive regulation of neuron differentiation Inferred from electronic annotation. Source: Compara positive regulation of translation Inferred from electronic annotation. Source: Compara pre-miRNA processing Inferred from mutant phenotype Ref.12Ref.13. Source: UniProtKB regulation of gene silencing by miRNA Inferred from electronic annotation. Source: Compara regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: InterPro stem cell maintenance Inferred from mutant phenotype Ref.13. Source: UniProtKB
Cellular_component	cytoplasmic mRNA processing body Inferred from direct assay Ref.11. Source: UniProtKB cytoplasmic stress granule Inferred from direct assay Ref.11. Source: UniProtKB nucleolus Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay Ref.11. Source: UniProtKB
Molecular_function	DNA binding Inferred from electronic annotation. Source: InterPro RNA binding Inferred from direct assay Ref.12Ref.13. Source: UniProtKB mRNA binding Inferred from electronic annotation. Source: Compara miRNA binding Inferred from electronic annotation. Source: Compara zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.15

Chain

2 – 209

208

Protein lin-28 homolog A

PRO_0000253787

Regions

Domain

39 – 112

74

CSD

Zinc finger

137 – 154

18

CCHC-type 1

Zinc finger

159 – 176

18

CCHC-type 2

Region

113 – 136

24

Flexible linker

Amino acid modifications

Modified residue

2

1

N-acetylglycine Ref.15

Modified residue

3

1

Phosphoserine Ref.15

Modified residue

120

1

Phosphoserine Ref.15

Modified residue

200

1

Phosphoserine Ref.15

Experimental info

Mutagenesis

46

1

W → A: Does not affect localization to cytoplasmic processing bodies; when associated with A-55 and A-73. Ref.11

Mutagenesis

55

1

F → A: Does not affect localization to cytoplasmic processing bodies; when associated with A-46 and A-73. Ref.11

Mutagenesis

73

1

F → A: Does not affect localization to cytoplasmic processing bodies; when associated with A-46 and A-55. Ref.11

Mutagenesis

147

1

H → A: Abolishes ability to suppress pre-let-7 biogenesis and localization to cytoplasmic processing bodies without affecting pre-let-7 binding; when associated with A-169. Ref.11 Ref.12

Mutagenesis

169

1

H → A: Abolishes ability to suppress pre-let-7 biogenesis and localization to cytoplasmic processing bodies without affecting pre-let-7 binding; when associated with A-147. Ref.11 Ref.12

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

209

Helix Strand Turn

Details...

Beta strand

140 – 142

3

Beta strand

145 – 147

3

Turn

149 – 151

3

Turn

162 – 164

3

Beta strand

167 – 169

3

Turn

171 – 173

3

Helix

176 – 178

3

Sequences

	Sequence		Length	Mass (Da)
	Q9H9Z2 [UniParc]. Last modified March 1, 2001. Version 1. Checksum: FA5EF6DD33FABF54	FASTA	209	22,743
	10 20 30 40 50 60 MGSVSNQQFA GGCAKAAEEA PEEAPEDAAR AADEPQLLHG AGICKWFNVR MGFGFLSMTA 70 80 90 100 110 120 RAGVALDPPV DVFVHQSKLH MEGFRSLKEG EAVEFTFKKS AKGLESIRVT GPGGVFCIGS 130 140 150 160 170 180 ERRPKGKSMQ KRRSKGDRCY NCGGLDHHAK ECKLPPQPKK CHFCQSISHM VASCPLKAQQ 190 200 GPSAQGKPTY FREEEEEIHS PTLLPEAQN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites." Moss E.G., Tang L. Dev. Biol. 258:432-442(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	Erratum Moss E.G., Tang L. Dev. Biol. 262:361-361(2003)
[3]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Teratocarcinoma.
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [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]	"Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation." Sempere L.F., Freemantle S., Pitha-Rowe I., Moss E.G., Dmitrovsky E., Ambros V. Genome Biol. 5:R13.1-R13.11(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[7]	"The transcriptome profile of human embryonic stem cells as defined by SAGE." Richards M., Tan S.-P., Tan J.-H., Chan W.-K., Bongso A. Stem Cells 22:51-64(2004) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
[8]	"Vascular gene expression and phenotypic correlation during differentiation of human embryonic stem cells." Gerecht-Nir S., Dazard J.-E., Golan-Mashiach M., Osenberg S., Botvinnik A., Amariglio N., Domany E., Rechavi G., Givol D., Itskovitz-Eldor J. Dev. Dyn. 232:487-497(2005) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
[9]	"Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation." Lee Y.S., Kim H.K., Chung S., Kim K.-S., Dutta A. J. Biol. Chem. 280:16635-16641(2005) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
[10]	"Micro-RNA regulation of the mammalian lin-28 gene during neuronal differentiation of embryonal carcinoma cells." Wu L., Belasco J.G. Mol. Cell. Biol. 25:9198-9208(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[11]	"Localization of the developmental timing regulator Lin28 to mRNP complexes, P-bodies and stress granules." Balzer E., Moss E.G. RNA Biol. 4:16-25(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF TRP-46; PHE-55; PHE-73; HIS-147 AND HIS-169.
[12]	"Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA." Heo I., Joo C., Cho J., Ha M., Han J., Kim V.N. Mol. Cell 32:276-284(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, RNA-BINDING, MUTAGENESIS OF HIS-147 AND HIS-169.
[13]	"TUT4 in concert with Lin28 suppresses MicroRNA biogenesis through pre-microRNA uridylation." Heo I., Joo C., Kim Y.-K., Ha M., Yoon M.-J., Cho J., Yeom K.-H., Han J., Kim V.N. Cell 138:696-708(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, RNA-BINDING, INTERACTION WITH ZCCHC11.
[14]	"Lin28 promotes transformation and is associated with advanced human malignancies." Viswanathan S.R., Powers J.T., Einhorn W., Hoshida Y., Ng T.L., Toffanin S., O'Sullivan M., Lu J., Phillips L.A., Lockhart V.L., Shah S.P., Tanwar P.S., Mermel C.H., Beroukhim R., Azam M., Teixeira J., Meyerson M., Hughes T.P. , Llovet J.M., Radich J., Mullighan C.G., Golub T.R., Sorensen P.H., Daley G.Q. Nat. Genet. 41:843-848(2009) [PubMed] [Europe PMC] [Abstract] Cited for: POSSIBLE INVOLVEMENT IN CANCERS.
[15]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT GLY-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; SER-120 AND SER-200, MASS SPECTROMETRY, CLEAVAGE OF INITIATOR METHIONINE.
[16]	"Solution structure of the zinc-finger domain in LIN-28." RIKEN structural genomics initiative (RSGI) Submitted (NOV-2005) to the PDB data bank Cited for: STRUCTURE BY NMR OF 134-186.
[17]	"Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28." Loughlin F.E., Gebert L.F., Towbin H., Brunschweiger A., Hall J., Allain F.H. Nat. Struct. Mol. Biol. 19:84-89(2012) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 124-186 IN COMPLEX WITH SHORT RNA, CONSENSUS MOTIF.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF521099 mRNA. Translation: AAM77751.1.
AK022519 mRNA. Translation: BAB14075.1.
AL513365 Genomic DNA. Translation: CAI21500.1.
BC028566 mRNA. Translation: AAH28566.1.

IPI

IPI00002948.

RefSeq

NP_078950.1. NM_024674.4.

UniGene

Hs.86154.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2CQF	NMR	-	A	136-186	[»]
2LI8	NMR	-	A	124-186	[»]

ProteinModelPortal

Q9H9Z2.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9H9Z2. 1 interaction.

STRING

9606.ENSP00000254231.

PTM databases

PhosphoSite

Q9H9Z2.

Polymorphism databases

DMDM

74752750.

Proteomic databases

PaxDb

Q9H9Z2.

PRIDE

Q9H9Z2.

Protocols and materials databases

DNASU

79727.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000254231; ENSP00000254231; ENSG00000131914.
ENST00000326279; ENSP00000363314; ENSG00000131914.

GeneID

79727.

KEGG

hsa:79727.

UCSC

uc001bmj.3. human.

Organism-specific databases

CTD

79727.

GeneCards

GC01P026737.

HGNC

HGNC:15986. LIN28A.

HPA

CAB020785.

MIM

611043. gene.

neXtProt

NX_Q9H9Z2.

PharmGKB

PA165751523.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG244191.

HOGENOM

HOG000047091.

HOVERGEN

HBG081922.

InParanoid

Q9H9Z2.

OMA

GVGVCKW.

OrthoDB

EOG4640D4.

PhylomeDB

Q9H9Z2.

Gene expression databases

Bgee

Q9H9Z2.

CleanEx

HS_LIN28.

Genevestigator

Q9H9Z2.

GermOnline

ENSG00000131914. Homo sapiens.

Family and domain databases

Gene3D

2.40.50.140. 1 hit.
4.10.60.10. 1 hit.

InterPro

IPR011129. Cold_shock_prot.
IPR002059. CSP_DNA-bd.
IPR012340. NA-bd_OB-fold.
IPR001878. Znf_CCHC.
[Graphical view]

Pfam

PF00313. CSD. 1 hit.
PF00098. zf-CCHC. 1 hit.
[Graphical view]

PRINTS

PR00050. COLDSHOCK.

SMART

SM00357. CSP. 1 hit.
SM00343. ZnF_C2HC. 2 hits.
[Graphical view]

SUPFAM

SSF50249. Nucleic_acid_OB. 1 hit.
SSF57756. SSF57756. 1 hit.

PROSITE

PS50158. ZF_CCHC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q9H9Z2.

GenomeRNAi

79727.

NextBio

69098.

SOURCE

Search...

Entry information

Entry name

LN28A_HUMAN

Accession

Primary (citable) accession number: Q9H9Z2

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 17, 2006
Last sequence update:	March 1, 2001
Last modified:	May 1, 2013
This is version 105 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.