DF/HCC Program Affiliation

Leukemia
Cancer Cell Biology

Research Abstract

STRUCTURE AND FUNCTION OF TRANSMEMBRANE RECEPTORS

Keywords: lipoprotein receptor, protein structure, Notch, Notch1, nuclear magnetic resonance, protein dynamics.

The long-term goal of our research program 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. The current working model for signaling by Notch receptors is that ligand binding triggers 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. The overarching goal of our studies is to elucidate the molecular logic of Notch signaling in different developmental, physiologic, and pathophysiologic contexts. To achieve this goal, we are combining biochemical, molecular, and structural approaches to gain insight into the mechanism of activation of Notch signaling. Our studies focus on three key steps in activation of Notch signals: how does the receptor recognize ligands, how is metalloprotease cleavage prevented prior to ligand binding, and how do the nuclear complexes assemble to activate transcription of target genes?

Publications

• Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC.Structural basis for autoinhibition of Notch.Nat Struct Mol Biol 2007 Apr;14(4):295-300.
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• Nam Y, Sliz P, Pear WS, Aster JC, Blacklow SC.Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription.Proc Natl Acad Sci U S A 2007 Feb 13;104(7):2103-8.
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• Nam Y, Sliz P, Song L, Aster JC, Blacklow SC.Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.Cell 2006 Mar 10;124(5):973-83.
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• Jeon H, Blacklow SC.Structure and physiologic function of the low-density lipoprotein receptor.Annu Rev Biochem 2005;74:535-62.
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• Beglova N, Jeon H, Fisher C, Blacklow SC.Cooperation between fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor.Mol Cell 2004 Oct 22;16(2):281-92.
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• Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC.Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair.Nat Struct Biol 2001 Jun;8(6):499-504.
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