MamL-1 domain explained

Symbol:MamL-1
MamL-1
Pfam:PF09596
Interpro:IPR019082

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]

Domain

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.

Notes and References

  1. McElhinny AS, Li JL, Wu L . Mastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways . Oncogene . 27 . 38 . 5138–47 . September 2008 . 18758483 . 10.1038/onc.2008.228 . free .
  2. Kovall RA . More complicated than it looks: assembly of Notch pathway transcription complexes . Oncogene . 27 . 38 . 5099–109 . September 2008 . 18758478 . 10.1038/onc.2008.223 .
  3. Schroeter EH, Kisslinger JA, Kopan R . Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain . . 393 . 6683 . 382–6 . May 1998 . 9620803 . 10.1038/30756 . 4431882 .
  4. Wilson JJ, Kovall RA . Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA . . 124 . 5 . 985–96 . March 2006 . 16530045 . 10.1016/j.cell.2006.01.035 . 9224353 . free .
  5. Chiang MY, Xu ML, Histen G, Shestova O, Roy M, Nam Y, Blacklow SC, Sacks DB, Pear WS, Aster JC . Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1 . Mol. Cell. Biol. . 26 . 16 . 6261–71 . August 2006 . 16880534 . 1592797 . 10.1128/MCB.02478-05 .
  6. Wu L, Maillard I, Nakamura M, Pear WS, Griffin JD . The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development . Blood . 110 . 10 . 3618–23 . November 2007 . 17699740 . 2077311 . 10.1182/blood-2007-06-097030 .
  7. Liu H, Kennard S, Lilly B . NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1 . Circ. Res. . 104 . 4 . 466–75 . February 2009 . 19150886 . 2747310 . 10.1161/CIRCRESAHA.108.184846 .
  8. Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, Griffin JD . Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation . EMBO J. . 24 . 13 . 2391–402 . July 2005 . 15961999 . 1173159 . 10.1038/sj.emboj.7600719 .
  9. Fryer CJ, White JB, Jones KA . Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover . Mol. Cell . 16 . 4 . 509–20 . November 2004 . 15546612 . 10.1016/j.molcel.2004.10.014 . free .
  10. Shen H, McElhinny AS, Cao Y, Gao P, Liu J, Bronson R, Griffin JD, Wu L . 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 . March 2006 . 16510869 . 1413284 . 10.1101/gad.1383706 .
  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 . The notch regulator MAML1 interacts with p53 and functions as a coactivator . J. Biol. Chem. . 282 . 16 . 11969–81 . April 2007 . 17317671 . 10.1074/jbc.M608974200 . free .
  12. Alves-Guerra MC, Ronchini C, Capobianco AJ . 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 . September 2007 . 17875709 . 10.1158/0008-5472.CAN-07-1720 .

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