Stephen C. Blacklow

Department of Pathology
Brigham and Women's Hospital
New Research Building, Room 652d
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 525-4413
Fax: (617) 525-4414
Email: sblacklow@rics.bwh.harvard.edu
Web Page: The Blacklow Lab Page
5 postdoctoral fellows, 5 graduate students

The long-term goal of the laboratory is to elucidate the detailed molecular basis for specificity in protein-protein and receptor-ligand interactions, focusing on proteins implicated in human disease. Over the next several years, the laboratory will continue to explore structure-function relationships in proteins of the vascular and hematopoetic systems, with particular emphasis on lipoprotein and Notch receptors.

Lipoprotein receptors. The LDL receptor (LDLR) is the primary mechanism for uptake of cholesterol-carrying lipoprotein particles into cells, and serves as a prototype for a large family of cell surface receptors implicated in biological processes ranging from lipoprotein uptake to Wnt signal transduction. The basis for ligand recognition by the LDLR and related receptors remains poorly understood. We intend to elucidate at a detailed biochemical level how lipoprotein receptors bind to and release their ligands, and understand how other related receptors of this family transmit biological signals.

Mechanism of signal transduction by the human Notch1 receptor. Human Notch1 is a modular, single-pass transmembrane receptor that normally controls cellular differentiation in hematopoetic (and other) cells. Ligand binding induces Notch signaling by triggering a cascade of proteolytic cleavages that release the intracellular portion of Notch from the membrane, allowing it to migrate to the nucleus where it activates transcription of Notch-responsive genes. Although Notch receptors are large and complex, all family members contain an extracellular ligand-binding domain, a conserved extracellular juxtamembrane region that maintains the receptor in a resting conformation prior to ligand-induced activation, and an intracellular ankyrin repeat domain required to activate transcription. Mutations in this juxtamembrane region cause increased signaling and occur frequently in human T-cell acute leukemias (T-ALL), identifying Notch as a therapeutic target in these tumors. We are using structural, biochemical and cell-based approaches to elucidate how Notch receptors are maintained in a resting conformation prior to ligand activation, and to understand how complexes that contain the intraceullular portion of Notch induce transcription of Notch target genes.

References:

• Nam, Y., Sliz, P., Song, L., Aster, JC, and Blacklow, SC. Structural basis for cooperativity in recruitment of MAML co-activators to Notch transcription complexes. Cell, 2006; 124, 973-983.
• Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269-71.
• Fisher C, Beglova N, Blacklow SC. Structure of an LDLR-RAP Complex Reveals a General Mode for Ligand Recognition by Lipoprotein Receptors. Molecular Cell 2006;22(2):277-83.
• Beglova, N., Jeon, H, Fisher, C. and Blacklow, SC. Cooperation of fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor. Molecular Cell 2004; 6(2):281-92.