[LIN12_CAEEL] Involved in several cell fate decisions that require cell-cell interactions. It is possible that lin-12 encodes a membrane-bound receptor for a signal that enables expression of the ventral uterine precursor cell fate. Activity in cell fate decisions and tumorigenesis is negatively regulated by sel-10.
The Notch pathway is a conserved cell-to-cell signaling mechanism, in which extracellular signals are transduced into transcriptional outputs through the nuclear effector CSL. CSL is converted from a repressor to an activator through the formation of the CSL-NotchIC-Mastermind ternary complex. The RAM (RBP-J associated molecule) domain of NotchIC avidly interacts with CSL; however, its role in assembly of the CSL-NotchIC-Mastermind ternary complex is not understood. Here we provide a comprehensive thermodynamic, structural, and biochemical analysis of the RAM-CSL interaction for components from both mouse and worm. Our binding data show that RAM and CSL form a high affinity complex in the presence or absence of DNA. Our structural studies reveal a striking distal conformational change in CSL upon RAM binding, which creates a docking site for Mastermind to bind to the complex. Finally, we show that the addition of a RAM peptide in trans facilitates formation of the CSL-NotchIC-Mastermind ternary complex in vitro.
RAM-induced allostery facilitates assembly of a notch pathway active transcription complex.,Friedmann DR, Wilson JJ, Kovall RA J Biol Chem. 2008 May 23;283(21):14781-91. Epub 2008 Apr 1. PMID:18381292
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Yochem J, Weston K, Greenwald I. The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch. Nature. 1988 Oct 6;335(6190):547-50. PMID:3419531 doi:http://dx.doi.org/10.1038/335547a0
↑ Greenwald I. lin-12, a nematode homeotic gene, is homologous to a set of mammalian proteins that includes epidermal growth factor. Cell. 1985 Dec;43(3 Pt 2):583-90. PMID:3000611
↑ Friedmann DR, Wilson JJ, Kovall RA. RAM-induced allostery facilitates assembly of a notch pathway active transcription complex. J Biol Chem. 2008 May 23;283(21):14781-91. Epub 2008 Apr 1. PMID:18381292 doi:http://dx.doi.org/10.1074/jbc.M709501200