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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4381-4390. Prepublished online as a Blood First Edition Paper on December 15, 2008; DOI 10.1182/blood-2008-08-174748. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2008-08-174748v1 113/18/4381    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gordon, W. R. Articles by Blacklow, S. C. Search for Related Content PubMed PubMed Citation Articles by Gordon, W. R. Articles by Blacklow, S. C. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL Wendy R. Gordon1, Monideepa Roy1, Didem Vardar-Ulu2, Megan Garfinkel1, Marc R. Mansour3, Jon C. Aster1, and Stephen C. Blacklow1 1 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA; 2 Department of Chemistry, Wellesley College, MA; and 3 Department of Haematology, Cancer Institute, University College London, London, United Kingdom Proteolytic resistance of Notch prior to ligand binding depends on the structural integrity of a negative regulatory region (NRR) of the receptor that immediately precedes the transmembrane segment. The NRR includes the 3 Lin12/Notch repeats and the juxtamembrane heterodimerization domain, the region of Notch1 most frequently mutated in T-cell acute lymphoblastic leukemia lymphoma (T-ALL). Here, we report the x-ray structure of the Notch1 NRR in its autoinhibited conformation. A key feature of the Notch1 structure that maintains its closed conformation is a conserved hydrophobic plug that sterically occludes the metalloprotease cleavage site. Crystal packing interactions involving a highly conserved, exposed face on the third Lin12/Notch repeat suggest that this site may normally be engaged in intermolecular or intramolecular protein-protein interactions. The majority of known T-ALL–associated point mutations map to residues in the hydrophobic interior of the Notch1 NRR. A novel mutation (H1545P), which alters a residue at the crystal-packing interface, leads to ligand-independent increases in signaling in reporter gene assays despite only mild destabilization of the NRR, suggesting that it releases the autoinhibitory clamp on the heterodimerization domain imposed by the Lin12/Notch repeats. The Notch1 NRR structure should facilitate a search for antibodies or compounds that stabilize the autoinhibited conformation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. van Tetering, P. van Diest, I. Verlaan, E. van der Wall, R. Kopan, and M. Vooijs Metalloprotease ADAM10 Is Required for Notch1 Site 2 Cleavage J. Biol. Chem., November 6, 2009; 284(45): 31018 - 31027. [Abstract] [Full Text] [PDF] E. C. Bozkulak and G. Weinmaster Selective Use of ADAM10 and ADAM17 in Activation of Notch1 Signaling Mol. Cell. Biol., November 1, 2009; 29(21): 5679 - 5695. [Abstract] [Full Text] [PDF]

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