MamL-1 domain

MamL-1
Identifiers
Symbol	MamL-1
Pfam	PF09596
InterPro	IPR019082
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

In molecular biology there are a number of neurogenic proteins referred to as mastermind-like proteins (MAMLs) of which this domain is the N-terminal region. Mastermind-like proteins act as critical transcriptional co-activators for Notch signaling.^[1][2]

The N-terminal domain of MAML proteins, MAML1, MAML2, MAML3, is a polypeptide of up to 70 residues, numbers 15-67 of which adopt an elongated kinked helix that wraps around ANK and CSL^[3][4] forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors. This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1,^[5] NOTCH2,^[6] NOTCH3^[7] and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP^[8] and CDK8.^[9] The C-terminal region is required for transcriptional activation.

Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C),^[10] tumour suppressor pathway (p53)^[11] and colon carcinoma survival (beta-catenin).^[12] MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.

References

1. ^ McElhinny AS, Li JL, Wu L (September 2008). "Mastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways". Oncogene 27 (38): 5138–47. doi:10.1038/onc.2008.228. PMID 18758483. 
2. ^ Kovall RA (September 2008). "More complicated than it looks: assembly of Notch pathway transcription complexes". Oncogene 27 (38): 5099–109. doi:10.1038/onc.2008.223. PMID 18758478. 
3. ^ Schroeter EH, Kisslinger JA, Kopan R (May 1998). "Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain". Nature 393 (6683): 382–6. doi:10.1038/30756. PMID 9620803. 
4. ^ Wilson JJ, Kovall RA (March 2006). "Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA". Cell 124 (5): 985–96. doi:10.1016/j.cell.2006.01.035. PMID 16530045. 
5. ^ Chiang MY, Xu ML, Histen G, Shestova O, Roy M, Nam Y, Blacklow SC, Sacks DB, Pear WS, Aster JC (August 2006). "Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1". Mol. Cell. Biol. 26 (16): 6261–71. doi:10.1128/MCB.02478-05. PMC 1592797. PMID 16880534. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1592797. 
6. ^ Wu L, Maillard I, Nakamura M, Pear WS, Griffin JD (November 2007). "The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development". Blood 110 (10): 3618–23. doi:10.1182/blood-2007-06-097030. PMC 2077311. PMID 17699740. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2077311. 
7. ^ Liu H, Kennard S, Lilly B (February 2009). "NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1". Circ. Res. 104 (4): 466–75. doi:10.1161/CIRCRESAHA.108.184846. PMC 2747310. PMID 19150886. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2747310. 
8. ^ Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, Griffin JD (July 2005). "Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation". EMBO J. 24 (13): 2391–402. doi:10.1038/sj.emboj.7600719. PMC 1173159. PMID 15961999. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1173159. 
9. ^ Fryer CJ, White JB, Jones KA (November 2004). "Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover". Mol. Cell 16 (4): 509–20. doi:10.1016/j.molcel.2004.10.014. PMID 15546612. 
10. ^ Shen H, McElhinny AS, Cao Y, Gao P, Liu J, Bronson R, Griffin JD, Wu L (March 2006). "The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis". Genes Dev. 20 (6): 675–88. doi:10.1101/gad.1383706. PMC 1413284. PMID 16510869. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1413284. 
11. ^ Zhao Y, Katzman RB, Delmolino LM, Bhat I, Zhang Y, Gurumurthy CB, Germaniuk-Kurowska A, Reddi HV, Solomon A, Zeng MS, Kung A, Ma H, Gao Q, Dimri G, Stanculescu A, Miele L, Wu L, Griffin JD, Wazer DE, Band H, Band V (April 2007). "The notch regulator MAML1 interacts with p53 and functions as a coactivator". J. Biol. Chem. 282 (16): 11969–81. doi:10.1074/jbc.M608974200. PMID 17317671. 
12. ^ Alves-Guerra MC, Ronchini C, Capobianco AJ (September 2007). "Mastermind-like 1 Is a specific coactivator of beta-catenin transcription activation and is essential for colon carcinoma cell survival". Cancer Res. 67 (18): 8690–8. doi:10.1158/0008-5472.CAN-07-1720. PMID 17875709. 

This article includes text from the public domain Pfam and InterPro IPR019082