Tr4
Mastermind‑like (MAML) is a glutamine-rich nuclear protein essential forNotch signaling activation. MAML is a co‑activator for all four Notch receptors. Mastermind complexes with the intracellular portion of activated Notch (NICD), the transcription factor CBF1 and DNA. This results in the activation of the Notch target genes Hes and Hey which comprise a family of transcriptional repressors.
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Overall Structure of the MAML 1:NICD:CBF1:DNA Complex. (A and B) Molecular surface representation. (C and D) Ribbon representation. Two views related by a 90 degree rotation are shown. The Notch intracellular domain (NICD) is colored purple. The Mastermind 1 (MAML 1) polypeptide is colored dark green. The N-terminal Rel Homology Region (RHR N), DNA binding -trefoil (BT), and the C-terminal RHR C domains of CBF1 are colored light brown, gold, and orange, respectively. The two DNA strands are colored blue and cyan. |
However, a truncated version of MAML that canmaintain an association with the complex, behaves in a dominantnegative (DN) fashion and inhibits Notch activation. DN-MAML consists of a 62‑amino‑acid kinked α‑helix that forms a stable ternary complex through contacts on both CBF1 and the ankyrin repeats of Notch1 but which lacks the C‑terminal portions of MAML1 that are responsible for Notch activation.
We have genetically engineered a fusion protein, consisting of Antennapedia/DN‑MAML, which will be tested for its ability to target tumor cells in vivo.