| Structural highlights
Disease
[MACD1_HUMAN] A chromosomal aberration involving MACROD1 is found in acute leukemia. Translocation t(11;21)(q13;q22) that forms a RUNX1-MACROD1 fusion protein.
Function
[MACD1_HUMAN] Removes ADP-ribose from glutamate residues in proteins bearing a single ADP-ribose moiety. Inactive towards proteins bearing poly-ADP-ribose. 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.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
MacroD1 is an enzyme that hydrolyzes protein mono-ADP-ribosylation. However, the key catalytic residues of MacroD1 in these biochemical reactions remain elusive. Here, we present the crystal structure of MacroD1 in a complex with ADP-ribose (ADPR). The beta5-alpha10-loop functions as a switch loop to mediate substrate recognition and right orientation. The conserved Phe(272) in the beta5-alpha10-loop plays a crucial role in the orientation of ADPR distal ribose, and a conserved hydrogen-bond network contributes significantly to hold and orient the catalytic water12, which mediates ADPR hydrolysis. Moreover, we found that MacroD1 was recruited to the sites of DNA damage via recognition of ADP-ribosylation at DNA lesions. The MacroD1-mediated ADPR hydrolysis is essential for DNA damage repair. Taken together, our study provides structural and functional insights into the molecular mechanism of MacroD1-mediated ADPR hydrolysis and its role in DNA damage repair.
Molecular basis for the MacroD1-mediated hydrolysis of ADP-ribosylation.,Yang X, Ma Y, Li Y, Dong Y, Yu LL, Wang H, Guo L, Wu C, Yu X, Liu X DNA Repair (Amst). 2020 Oct;94:102899. doi: 10.1016/j.dnarep.2020.102899. Epub, 2020 Jun 22. PMID:32683309[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Meng YG, Han WD, Zhao YL, Huang K, Si YL, Wu ZQ, Mu YM. Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherin. Cell Res. 2007 Oct;17(10):869-80. PMID:17893710 doi:http://dx.doi.org/10.1038/cr.2007.79
- ↑ Han WD, Zhao YL, Meng YG, Zang L, Wu ZQ, Li Q, Si YL, Huang K, Ba JM, Morinaga H, Nomura M, Mu YM. Estrogenically regulated LRP16 interacts with estrogen receptor alpha and enhances the receptor's transcriptional activity. Endocr Relat Cancer. 2007 Sep;14(3):741-53. PMID:17914104 doi:http://dx.doi.org/10.1677/ERC-06-0082
- ↑ Yang J, Zhao YL, Wu ZQ, Si YL, Meng YG, Fu XB, Mu YM, Han WD. The single-macro domain protein LRP16 is an essential cofactor of androgen receptor. Endocr Relat Cancer. 2009 Mar;16(1):139-53. doi: 10.1677/ERC-08-0150. Epub 2008, Nov 20. PMID:19022849 doi:http://dx.doi.org/10.1677/ERC-08-0150
- ↑ Tian L, Wu Z, Zhao Y, Meng Y, Si Y, Fu X, Mu Y, Han W. Differential induction of LRP16 by liganded and unliganded estrogen receptor alpha in SKOV3 ovarian carcinoma cells. J Endocrinol. 2009 Jul;202(1):167-77. doi: 10.1677/JOE-09-0054. Epub 2009 Apr 29. PMID:19403568 doi:http://dx.doi.org/10.1677/JOE-09-0054
- ↑ Jankevicius G, Hassler M, Golia B, Rybin V, Zacharias M, Timinszky G, Ladurner AG. A family of macrodomain proteins reverses cellular mono-ADP-ribosylation. Nat Struct Mol Biol. 2013 Apr;20(4):508-14. doi: 10.1038/nsmb.2523. Epub 2013 Mar, 10. PMID:23474712 doi:http://dx.doi.org/10.1038/nsmb.2523
- ↑ Chen D, Vollmar M, Rossi MN, Phillips C, Kraehenbuehl R, Slade D, Mehrotra PV, von Delft F, Crosthwaite SK, Gileadi O, Denu JM, Ahel I. Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases. J Biol Chem. 2011 Apr 15;286(15):13261-71. Epub 2011 Jan 21. PMID:21257746 doi:10.1074/jbc.M110.206771
- ↑ Yang X, Ma Y, Li Y, Dong Y, Yu LL, Wang H, Guo L, Wu C, Yu X, Liu X. Molecular basis for the MacroD1-mediated hydrolysis of ADP-ribosylation. DNA Repair (Amst). 2020 Oct;94:102899. doi: 10.1016/j.dnarep.2020.102899. Epub, 2020 Jun 22. PMID:32683309 doi:http://dx.doi.org/10.1016/j.dnarep.2020.102899
|
