Chris Veldkamp
Bachelors in Chemistry
Taylor University
Project: Structural Basis For Chemokine Signaling
Advisor: Dr Brian Volkman
The goal of this project is to understand the structural and functional requirements for chemokine signaling.
Chemokines are small, secreted proteins that mediate inflammation, stem cell homing, and early embryonic
development by providing directional cues to migrating cells. The 50 known chemokines induce chemotaxis
by specifically activating members of a group of 20 G-protein coupled receptors, which are integral membrane
proteins containing seven transmembrane alpha helices. A chemokine concentration gradient maintained by
interactions with extracellular matrix glycosaminoglycans is also needed to induce chemotactic responses
in vivo, and, for some chemokines, formation of homodimeric structures is also a functional requirement.
Stromal cell-derived factor-1 (SDF1) and its cognate receptor CXCR4 comprise a chemokine signaling system
that is exploited by metastatic cancers and HIV/AIDS. T-tropic HIV-1 gains entry into T cells through specific
binding to CXCR4, a process that is inhibited by the chemokine SDF1. Cancer cells that express CXCR4 and
escape the primary tumor environment travel the circulatory and lymphatic systems homing in on a select group
of tissues that produce high levels of SDF1, including bone marrow, lung, and lymph nodes. A complete model
for chemokine function at a molecular level must include GPCR activation, glycosaminoglycan binding, and dimer
formation. NMR and fluorescence spectroscopy combined with mutagenesis studies and biological assays are
being used to characterize each of the specific biding interactions required for SDF1-CXCR4 signaling.
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