Q9BQ69 (MACD1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
MACRO domain-containing protein 1

Alternative name(s):
O-acetyl-ADP-ribose deacetylase
EC=3.5.1.-
Protein LRP16

Gene names

Name:	MACROD1
Synonyms:	LRP16

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

General annotation (Comments)

Function	Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins. Plays a role in estrogen signaling. Binds to androgen receptor (AR) and amplifies the transactivation function of AR in response to androgen. May play an important role in carcinogenesis and/or progression of hormone-dependent cancers by feed-forward mechanism that activates ESR1 transactivation. Could be an ESR1 coactivator, providing a positive feedback regulatory loop for ESR1 signal transduction. Could be involved in invasive growth by down-regulating CDH1 in endometrial cancer cells. Enhances ESR1-mediated transcription activity. Ref.4 Ref.5 Ref.7 Ref.8 Ref.11
Enzyme regulation	Subject to competitive inhibition by the product ADP-ribose. Ref.11
Subunit structure	Interacts with ESR1; Interacts in a manner that is estrogen independent but is enhanced by estrogen. Interacts (via macro domain) with AR. Ref.5 Ref.7
Induction	Overexpressed by estrogens in breast cancer MCF-7 cells, probably via an activation of nuclear receptors for steroids (ESR1 but not ESR2). Significantly increased by estrogens in ESR1-positive Ishikawa endometrial cancer cells. Up-regulated in 17-beta-estradiol-responsive BG-1 ovarian cancer cells but down-regulated in estrogen-resistant SKOV3 ovarian cancer cells. Induced by androgen. Ref.3 Ref.4 Ref.7 Ref.8 Ref.11
Involvement in disease	Note=A chromosomal aberration involving MACROD1 is found in acute leukemia. Translocation t(11;21)(q13;q22) that forms a RUNX1-MACROD1 fusion protein.
Miscellaneous	Overexpression may promote MCF-7 cells proliferation. There is an approximate one-third increase of the invasive capacity of MACROD1-overexpressing cells. The expression of CDH1 is repressed by MACROD1. Further analyzes demonstrats that MACROD1 inhibits CDH1 transactivation in a dose dependent manner. Inhibition is abolished by estrogen deprivation, indicating that the down-regulation of CDH1 transcription by MACROD1 requires ESR1 mediation. Binding of ESR1 to the CDH1 promoter is antagonized by MACROD1, suggesting that MACROD1 could interfere with ESR1-mediated transcription. Knockdown of MACROD1 leads to impaired AR function and greatly attenuates the coactivation of AR by other AR coactivators such as UXT and NCOA1. This interference also markedly inhibits the androgen-stimulated proliferation of androgen-sensitive LNCaP prostate cancer cells. MACROD1 knockdown does not significantly affect the growth rate of AR-negative PC-3 prostate cancer cells.
Sequence similarities	Contains 1 Macro domain.
Biophysicochemical properties	Kinetic parameters: KM=373 µM for O-acetyl-ADP-ribose Ref.11
Sequence caution	The sequence AAH03188.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence AAH03188.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Coding sequence diversity	Chromosomal rearrangement
Molecular function	Hydrolase
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	purine nucleoside metabolic process Inferred from direct assay Ref.11. Source: UniProtKB
Molecular function	deacetylase activity Inferred from direct assay Ref.11. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 325

325

MACRO domain-containing protein 1

PRO_0000084485

Regions

Domain

141 – 322

182

Macro

Region

267 – 273

7

Substrate binding Probable

Sites

Active site

184

1

Proton acceptor Potential

Site

100

1

Breakpoint for translocation to form RUNX1-MACROD1

Amino acid modifications

Modified residue

103

1

N6-acetyllysine Ref.9

Experimental info

Mutagenesis

160

1

D → A: Reduced enzyme activity. Ref.11

Mutagenesis

167

1

D → A: Reduced enzyme activity. Ref.11

Mutagenesis

171

1

N → A: Reduced enzyme activity. No significant effect on affinity for substrate. Ref.11

Mutagenesis

174

1

N → A: Reduced enzyme activity. Reduces enzyme activity by 93%; when associated with A-184. No significant effect on affinity for substrate. Ref.11

Mutagenesis

184

1

D → A: Reduced enzyme activity. Reduces enzyme activity by 93%; when associated with A-174. No significant effect on affinity for substrate. Ref.11

Mutagenesis

188

1

H → A: Reduced enzyme activity. Ref.11

Mutagenesis

268

1

S → A: No significant effect on enzyme activity. Ref.11

Mutagenesis

270

1

G → E: Loss of enzyme activity. Ref.11

Secondary structure

1

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325

Helix Strand Turn

Details...

Helix

94 – 103

10

Helix

107 – 110

4

Helix

111 – 113

3

Helix

122 – 124

3

Helix

128 – 132

5

Helix

148 – 151

4

Beta strand

154 – 159

6

Helix

161 – 163

3

Beta strand

164 – 172

9

Helix

187 – 190

4

Helix

194 – 200

7

Beta strand

210 – 213

4

Beta strand

218 – 226

9

Helix

237 – 256

20

Beta strand

261 – 264

4

Helix

276 – 294

19

Helix

295 – 297

3

Beta strand

299 – 305

7

Helix

308 – 321

14

Sequences

	Sequence		Length	Mass (Da)
	Q9BQ69 [UniParc]. Last modified June 16, 2003. Version 2. Checksum: 82294BFC904FA4D0	FASTA	325	35,505
	10 20 30 40 50 60 MSLQSRLSGR LAQLRAAGQL LVPPRPRPGH LAGATRTRSS TCGPPAFLGV FGRRARTSAG 70 80 90 100 110 120 VGAWGAAAVG RTAGVRTWAP LAMAAKVDLS TSTDWKEAKS FLKGLSDKQR EEHYFCKDFV 130 140 150 160 170 180 RLKKIPTWKE MAKGVAVKVE EPRYKKDKQL NEKISLLRSD ITKLEVDAIV NAANSSLLGG 190 200 210 220 230 240 GGVDGCIHRA AGPLLTDECR TLQSCKTGKA KITGGYRLPA KYVIHTVGPI AYGEPSASQA 250 260 270 280 290 300 AELRSCYLSS LDLLLEHRLR SVAFPCISTG VFGYPCEAAA EIVLATLREW LEQHKDKVDR 310 320 LIICVFLEKD EDIYRSRLPH YFPVA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The application of RACE technique to clone the full-length cDNA of a novel leukemia associated gene LRP16." Han W.-D., Yu L., Lou F.D., Wang Q.S., Zhao Y., Shi Z.J., Jin H.J. Zhongguo Shi Yan Xue Ye Xue Za Zhi 9:18-21(2001) [PubMed: 12578638] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lymphocyte.
[2]	"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: Brain and Eye.
[3]	"Up-regulation of LRP16 mRNA by 17beta-estradiol through activation of estrogen receptor alpha (ERalpha), but not ERbeta, and promotion of human breast cancer MCF-7 cell proliferation: a preliminary report." Han W.-D., Mu Y.-M., Lu X.-C., Xu Z.-M., Li X.-J., Yu L., Song H.-J., Li M., Lu J.-M., Zhao Y.-L., Pan C.-Y. Endocr. Relat. Cancer 10:217-224(2003) [PubMed: 12790785] [Abstract] Cited for: INDUCTION.
[4]	"Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherin." Meng Y.G., Han W.-D., Zhao Y.-L., Huang K., Si Y.-L., Wu Z.-Q., Mu Y.-M. Cell Res. 17:869-880(2007) [PubMed: 17893710] [Abstract] Cited for: INDUCTION, FUNCTION.
[5]	"Estrogenically regulated LRP16 interacts with estrogen receptor alpha and enhances the receptor's transcriptional activity." Han W.-D., Zhao Y.-L., Meng Y.G., Zang L., Wu Z.-Q., Li Q., Si Y.-L., Huang K., Ba J.-M., Morinaga H., Nomura M., Mu Y.-M. Endocr. Relat. Cancer 14:741-753(2007) [PubMed: 17914104] [Abstract] Cited for: INTERACTION WITH ESR1, FUNCTION.
[6]	"LRP16 is fused to RUNX1 in monocytic leukemia cell line with t(11;21)(q13;q22)." Imagama S., Abe A., Suzuki M., Hayakawa F., Katsumi A., Emi N., Kiyoi H., Naoe T. Eur. J. Haematol. 79:25-31(2007) [PubMed: 17532767] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH RUNX1.
[7]	"The single-macro domain protein LRP16 is an essential cofactor of androgen receptor." Yang J., Zhao Y.-L., Wu Z.-Q., Si Y.-L., Meng Y.G., Fu X.B., Mu Y.-M., Han W.-D. Endocr. Relat. Cancer 16:139-153(2009) [PubMed: 19022849] [Abstract] Cited for: FUNCTION, INTERACTION WITH ANDROGENE RECEPTOR, INDUCTION BY ANDROGEN.
[8]	"Differential induction of LRP16 by liganded and unliganded estrogen receptor alpha in SKOV3 ovarian carcinoma cells." Tian L., Wu Z., Zhao Y., Meng Y., Si Y., Fu X., Mu Y., Han W. J. Endocrinol. 202:167-177(2009) [PubMed: 19403568] [Abstract] Cited for: INDUCTION, FUNCTION.
[9]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-103, MASS SPECTROMETRY.
[10]	"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].
[11]	"Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases." Chen D., Vollmar M., Rossi M.N., Phillips C., Kraehenbuehl R., Slade D., Mehrotra P.V., von Delft F., Crosthwaite S.K., Gileadi O., Denu J.M., Ahel I. J. Biol. Chem. 286:13261-13271(2011) [PubMed: 21257746] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 91-325, FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-160; ASP-167; ASN-171; ASN-174; ASP-184; HIS-188; SER-268 AND GLY-270, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF202922 mRNA. Translation: AAF15294.2.
BC000270 mRNA. Translation: AAH00270.2.
BC003188 mRNA. Translation: AAH03188.1. Different initiation.
BC007297 mRNA. Translation: AAH07297.1.
BC008316 mRNA. Translation: AAH08316.1.

IPI

IPI00155601.

RefSeq

NP_054786.2. NM_014067.3.

UniGene

Hs.602898.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2X47	X-ray	1.70	A	91-325	[»]

ProteinModelPortal

Q9BQ69.

SMR

Q9BQ69. Positions 91-325.

ModBase

Search...

Protein-protein interaction databases

STRING

Q9BQ69.

PTM databases

PhosphoSite

Q9BQ69.

Polymorphism databases

DMDM

32129719.

Proteomic databases

PeptideAtlas

Q9BQ69.

PRIDE

Q9BQ69.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000255681; ENSP00000255681; ENSG00000133315.

GeneID

28992.

KEGG

hsa:28992.

UCSC

uc001nyh.1. human.

Organism-specific databases

CTD

28992.

GeneCards

GC11M063767.

H-InvDB

HIX0019413.

HGNC

HGNC:29598. MACROD1.

HPA

HPA041031.

MIM

610400. gene.

neXtProt

NX_Q9BQ69.

PharmGKB

PA162394816.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG08528.

GeneTree

ENSGT00520000055566.

HOGENOM

HBG682503.

HOVERGEN

HBG052356.

InParanoid

Q9BQ69.

OMA

TAGVRTW.

OrthoDB

EOG47SSDZ.

PhylomeDB

Q9BQ69.

Gene expression databases

ArrayExpress

Q9BQ69.

Bgee

Q9BQ69.

CleanEx

HS_MACROD1.

Genevestigator

Q9BQ69.

GermOnline

ENSG00000133315. Homo sapiens.

Family and domain databases

InterPro

IPR002589. A1pp.
[Graphical view]

Pfam

PF01661. Macro. 1 hit.
[Graphical view]

SMART

SM00506. A1pp. 1 hit.
[Graphical view]

PROSITE

PS51154. MACRO. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

51921.

SOURCE

Search...

Entry information

Entry name

MACD1_HUMAN

Accession

Primary (citable) accession number: Q9BQ69
Secondary accession number(s): Q9UH96

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 16, 2003
Last sequence update:	June 16, 2003
Last modified:	January 25, 2012
This is version 84 of the entry and version 2 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.