Q15797 (SMAD1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mothers against decapentaplegic homolog 1
Short name=MAD homolog 1
Short name=Mothers against DPP homolog 1

Alternative name(s):
JV4-1
Mad-related protein 1
SMAD family member 1
Short name=SMAD 1
Short name=Smad1
Short name=hSMAD1
Transforming growth factor-beta-signaling protein 1
Short name=BSP-1

Gene names

Name:	SMAD1
Synonyms:	BSP1, MADH1, MADR1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	465 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD1 is a receptor-regulated SMAD (R-SMAD). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. Ref.17
Subunit structure	Interacts with HGS, NANOG and ZCCHC12 By similarity. May form trimers with another SMAD1 and the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit, CREB-binding protein (CBP), p300, SMURF1, SMURF2 and HOXC8. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with SKOR1. Interacts (via MH2 domain) with LEMD3. Binding to LEMD3 results in at least a partial reduction of receptor-mediated phosphorylation. Forms a ternary complex with PSMB4 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Ref.14 Ref.18 Ref.19 Ref.20
Subcellular location	Cytoplasm. Nucleus. Note: Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with SMAD4. Co-localizes with LEMD3 at the nucleus inner membrane. Ref.19
Tissue specificity	Ubiquitous. Highest expression seen in the heart and skeletal muscle.
Post-translational modification	Phosphorylated on serine by BMP type 1 receptor kinase. Ref.11 Ref.22 Ubiquitin-mediated proteolysis by SMAD-specific E3 ubiquitin ligase SMURF1.
Involvement in disease	Defects in SMAD1 may be a cause of primary pulmonary hypertension (PPH1) [MIM:178600]. A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.
Sequence similarities	Belongs to the dwarfin/SMAD family. Contains 1 MH1 (MAD homology 1) domain. Contains 1 MH2 (MAD homology 2) domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Disease	Disease mutation
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	BMP signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB SMAD protein complex assembly Inferred from direct assay. Source: BHF-UCL embryonic pattern specification Inferred from sequence or structural similarity. Source: UniProtKB primary miRNA processing Traceable author statement. Source: BHF-UCL transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transforming growth factor beta receptor signaling pathway Non-traceable author statement Ref.4. Source: UniProtKB
Cellular component	cytosol Traceable author statement. Source: Reactome integral to membrane Non-traceable author statement Ref.4. Source: UniProtKB nuclear inner membrane Inferred from direct assay Ref.19. Source: UniProtKB
Molecular function	I-SMAD binding Inferred from physical interaction. Source: BHF-UCL co-SMAD binding Inferred from physical interaction. Source: BHF-UCL identical protein binding Inferred from physical interaction. Source: BHF-UCL protein kinase binding Inferred from physical interaction. Source: UniProtKB sequence-specific DNA binding transcription factor activity Inferred from direct assay. Source: BHF-UCL transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity Traceable author statement. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
YAP1	P46937	3	EBI-1567153,EBI-1044059

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 465

465

Mothers against decapentaplegic homolog 1

PRO_0000090847

Regions

Domain

12 – 136

125

MH1

Domain

271 – 465

195

MH2

Compositional bias

39 – 45

7

Poly-Lys

Compositional bias

198 – 201

4

Poly-Ser

Amino acid modifications

Modified residue

1

1

N-acetylmethionine Ref.10

Modified residue

322

1

Phosphothreonine; by MINK1, TNIK and MAP4K4 Ref.22

Modified residue

463

1

Phosphoserine Ref.11

Modified residue

465

1

Phosphoserine Ref.11

Natural variations

Natural variant

3

1

V → A in PPH1; affects SMAD-mediated signaling.

VAR_066869

Experimental info

Mutagenesis

419

1

G → S: Loss of phosphorylation. Ref.3

Secondary structure

1

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465

Helix Strand Turn

Details...

Beta strand

272 – 278

7

Beta strand

291 – 299

9

Beta strand

305 – 310

6

Helix

321 – 327

7

Beta strand

334 – 338

5

Beta strand

340 – 347

8

Beta strand

349 – 351

3

Beta strand

353 – 356

4

Helix

358 – 363

6

Beta strand

372 – 374

3

Beta strand

379 – 384

6

Helix

385 – 393

9

Turn

394 – 398

5

Helix

400 – 404

5

Helix

405 – 410

6

Beta strand

411 – 417

7

Helix

429 – 431

3

Beta strand

432 – 440

9

Helix

441 – 451

11

Sequences

	Sequence		Length	Mass (Da)
	Q15797 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 2DD34B7F434DBC7E	FASTA	465	52,260
	10 20 30 40 50 60 MNVTSLFSFT SPAVKRLLGW KQGDEEEKWA EKAVDALVKK LKKKKGAMEE LEKALSCPGQ 70 80 90 100 110 120 PSNCVTIPRS LDGRLQVSHR KGLPHVIYCR VWRWPDLQSH HELKPLECCE FPFGSKQKEV 130 140 150 160 170 180 CINPYHYKRV ESPVLPPVLV PRHSEYNPQH SLLAQFRNLG QNEPHMPLNA TFPDSFQQPN 190 200 210 220 230 240 SHPFPHSPNS SYPNSPGSSS STYPHSPTSS DPGSPFQMPA DTPPPAYLPP EDPMTQDGSQ 250 260 270 280 290 300 PMDTNMMAPP LPSEINRGDV QAVAYEEPKH WCSIVYYELN NRVGEAFHAS STSVLVDGFT 310 320 330 340 350 360 DPSNNKNRFC LGLLSNVNRN STIENTRRHI GKGVHLYYVG GEVYAECLSD SSIFVQSRNC 370 380 390 400 410 420 NYHHGFHPTT VCKIPSGCSL KIFNNQEFAQ LLAQSVNHGF ETVYELTKMC TIRMSFVKGW 430 440 450 460 GAEYHRQDVT STPCWIEIHL HGPLQWLDKV LTQMGSPHNP ISSVS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mad-related genes in the human." Riggins G.J., Thiagalingam S., Rosenblum E., Weinstein C.L., Kern S.E., Hamilton S.R., Willson J.K.V., Markowitz S.D., Kinzler K.W., Vogelstein B.V. Nat. Genet. 13:347-349(1996) [PubMed: 8673135] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"A human Mad protein acting as a BMP-regulated transcriptional activator." Liu F., Hata A., Baker J.C., Doody J., Carcamo J., Harland R.M., Massague J. Nature 381:620-623(1996) [PubMed: 8637600] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Kidney.
[3]	"MADR1, a MAD-related protein that functions in BMP2 signaling pathways." Hoodless P.A., Haerry T., Abdollah S., Stapleton M., O'Connor M.B., Attisano L., Wrana J.L. Cell 85:489-500(1996) [PubMed: 8653785] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF GLY-419.
[4]	"Serine phosphorylation, chromosomal localization, and transforming growth factor-beta signal transduction by human bsp-1." Lechleider R.J., de Caestecker M.P., Dehejia A., Polymeropoulos M.H., Roberts A.B. J. Biol. Chem. 271:17617-17620(1996) [PubMed: 8663601] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Mammary carcinoma.
[5]	"Receptor-associated Mad homologues synergize as effectors of the TGF-beta response." Zhang Y., Feng X.-H., Wu R.-Y., Derynck R. Nature 383:168-172(1996) [PubMed: 8774881] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[6]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Uterus.
[8]	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 (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[10]	Bienvenut W.V., Lempens A., Norman J.C. Submitted (OCT-2009) to UniProtKB Cited for: PROTEIN SEQUENCE OF 1-15; 33-39; 129-157; 283-306 AND 309-319, ACETYLATION AT MET-1, MASS SPECTROMETRY. Tissue: Ovarian carcinoma.
[11]	"The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase." Kretzschmar M., Liu F., Hata A., Doody J., Massague J. Genes Dev. 11:984-995(1997) [PubMed: 9136927] [Abstract] Cited for: PHOSPHORYLATION AT SER-463 AND SER-465.
[12]	"TGF-beta signal transduction." Massague J. Annu. Rev. Biochem. 67:753-791(1998) [PubMed: 9759503] [Abstract] Cited for: REVIEW.
[13]	"Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells." Verschueren K., Huylebroeck D. Cytokine Growth Factor Rev. 10:187-199(1999) [PubMed: 10647776] [Abstract] Cited for: REVIEW.
[14]	"OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways." Hata A., Seoane J., Lagna G., Montalvo E., Hemmati-Brivanlou A., Massague J. Cell 100:229-240(2000) [PubMed: 10660046] [Abstract] Cited for: INTERACTION WITH ZNF423.
[15]	"The Smad pathway." Wrana J.L., Attisano L. Cytokine Growth Factor Rev. 11:5-13(2000) [PubMed: 10708948] [Abstract] Cited for: REVIEW.
[16]	"TGF-beta signaling by Smad proteins." Miyazono K. Cytokine Growth Factor Rev. 11:15-22(2000) [PubMed: 10708949] [Abstract] Cited for: REVIEW.
[17]	"A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs)." Lin Y., Martin J., Gruendler C., Farley J., Meng X., Li B.-Y., Lechleider R., Huff C., Kim R.H., Grasser W.A., Paralkar V., Wang T. BMC Cell Biol. 3:15-15(2002) [PubMed: 12097147] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH PSMB4 AND OAZ1, FUNCTION.
[18]	"Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse Evi3, is highly expressed in primitive human hematopoietic cells." Bond H.M., Mesuraca M., Carbone E., Bonelli P., Agosti V., Amodio N., De Rosa G., Di Nicola M., Gianni A.M., Moore M.A., Hata A., Grieco M., Morrone G., Venuta S. Blood 103:2062-2070(2004) [PubMed: 14630787] [Abstract] Cited for: INTERACTION WITH ZNF521.
[19]	"The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines." Pan D., Estevez-Salmeron L.D., Stroschein S.L., Zhu X., He J., Zhou S., Luo K. J. Biol. Chem. 280:15992-16001(2005) [PubMed: 15647271] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH LEMD3.
[20]	"Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling." Arndt S., Poser I., Moser M., Bosserhoff A.-K. Mol. Cell. Neurosci. 34:603-611(2007) [PubMed: 17292623] [Abstract] Cited for: INTERACTION WITH SKOR1.
[21]	"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: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[22]	"Smad inhibition by the Ste20 kinase Misshapen." Kaneko S., Chen X., Lu P., Yao X., Wright T.G., Rajurkar M., Kariya K., Mao J., Ip Y.T., Xu L. Proc. Natl. Acad. Sci. U.S.A. 108:11127-11132(2011) [PubMed: 21690388] [Abstract] Cited for: PHOSPHORYLATION AT THR-322.
[23]	"Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension." Nasim M.T., Ogo T., Ahmed M., Randall R., Chowdhury H.M., Snape K.M., Bradshaw T.Y., Southgate L., Lee G.J., Jackson I., Lord G.M., Gibbs J.S., Wilkins M.R., Ohta-Ogo K., Nakamura K., Girerd B., Coulet F., Soubrier F. , Humbert M., Morrell N.W., Trembath R.C., Machado R.D. Hum. Mutat. 32:1385-1389(2011) [PubMed: 21898662] [Abstract] Cited for: VARIANT PPH1 ALA-3, CHARACTERIZATION OF VARIANT PPH1 ALA-3.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U59912 mRNA. Translation: AAC50790.1.
U59423 mRNA. Translation: AAB06852.1.
U54826 mRNA. Translation: AAC50493.1.
U57456 mRNA. Translation: AAC50621.1.
BT007386 mRNA. Translation: AAP36050.1.
AK293055 mRNA. Translation: BAF85744.1.
CH471056 Genomic DNA. Translation: EAX05037.1.
CH471056 Genomic DNA. Translation: EAX05038.1.
CH471056 Genomic DNA. Translation: EAX05040.1.
BC001878 mRNA. Translation: AAH01878.1.

IPI

IPI00019549.

PIR

S68987.

RefSeq

NP_001003688.1. NM_001003688.1.
NP_005891.1. NM_005900.2.

UniGene

Hs.604588.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1KHU	X-ray	2.50	A/B/C/D	248-465	[»]
2LAW	NMR	-	B	222-233	[»]
2LAX	NMR	-	B	201-209	[»]
2LAY	NMR	-	B	201-209	[»]
2LAZ	NMR	-	B	210-217	[»]
2LB0	NMR	-	B	208-217	[»]
2LB1	NMR	-	B	221-233	[»]

ProteinModelPortal

Q15797.

SMR

Q15797. Positions 9-132, 268-465.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q15797. 6 interactions.

MINT

MINT-244113.

STRING

Q15797.

PTM databases

PhosphoSite

Q15797.

Polymorphism databases

DMDM

13633915.

Proteomic databases

PRIDE

Q15797.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000302085; ENSP00000305769; ENSG00000170365.
ENST00000394092; ENSP00000377652; ENSG00000170365.

GeneID

4086.

KEGG

hsa:4086.

UCSC

uc003ikc.1. human.

Organism-specific databases

CTD

4086.

GeneCards

GC04P146402.

H-InvDB

HIX0004541.

HGNC

HGNC:6767. SMAD1.

HPA

CAB005389.

MIM

178600. phenotype.
601595. gene.

neXtProt

NX_Q15797.

PharmGKB

PA30524.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG06039.

GeneTree

ENSGT00600000084186.

HOGENOM

HBG443554.

HOVERGEN

HBG053353.

InParanoid

Q15797.

OMA

MAQDGSQ.

PhylomeDB

Q15797.

Enzyme and pathway databases

Pathway_Interaction_DB

bmppathway. BMP receptor signaling.

Reactome

REACT_111102. Signal Transduction.

Gene expression databases

ArrayExpress

Q15797.

Bgee

Q15797.

CleanEx

HS_SMAD1.

Genevestigator

Q15797.

GermOnline

ENSG00000170365. Homo sapiens.

Family and domain databases

InterPro

IPR013790. Dwarfin.
IPR003619. MAD_homology1_Dwarfin-type.
IPR013019. MAD_homology_MH1.
IPR017855. SMAD_dom-like.
IPR001132. SMAD_dom_Dwarfin-type.
IPR008984. SMAD_FHA_domain.
[Graphical view]

Gene3D

G3DSA:3.90.520.10. MAD_MH1. 1 hit.
G3DSA:2.60.200.10. MH2_Dwarfin-type. 1 hit.

KO

K04676.

PANTHER

PTHR13703. Dwarfin. 1 hit.

Pfam

PF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]

SMART

SM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]

SUPFAM

SSF56366. MAD_MH1. 1 hit.
SSF49879. SMAD_FHA. 1 hit.

PROSITE

PS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

16014.

SOURCE

Search...

Entry information

Entry name

SMAD1_HUMAN

Accession

Primary (citable) accession number: Q15797
Secondary accession number(s): A8KAJ0, D3DNZ9, Q16636

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	November 1, 1996
Last modified:	January 25, 2012
This is version 136 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.