The past several years have seen a rapid advancement in our understanding of how CXCR4 transmits the extracellular CXCL12 signal into intracellular signaling, which ultimately causes cell migration along with other signaling outcomes critical in both immune cell function and various cancers. We began this project uncertain as to the stoichiometry of CXCL12:CXCR4 binding, and through various functional and structural studies were able to settle on an early complex model with 1:1 stoichiometry (chapters 2&3). An improvement in our ability to model the CXCL12:CXCR4 complex was enabled by the solution of the vMIP-II:CXCR4 crystal structure by our laboratory soon after, and other landmarks in chemokine receptor structural determination (chapter 4) have allowed for a global understanding of chemokine:receptor structure to emerge. At this point the structural link between CXCL12 N-terminus binding and the more conserved intracellular aspects of CXCR4 activation is finally coming into view. In our latest soon to be submitted study, we provide functional evidence decisively supporting the orientation proposed in our current model, as well as revealing previously unrecognized complexity in the nature of CXCR4 activation (chapter 5). In chapter 6, we comprehensively discuss tentative but exciting possible explanations for evidence in our latest findings of greater complexity in chemokine:chemokine receptor signaling than has been appreciated.
We have progressed from a rough understanding of how CXCL12 activates CXCR4 to an experimentally validated full-length CXCL12:CXCR4 signaling complex model. Ultimately, we have made significant contributions to understanding the structure of CXCR4 bound to CXCL12, the precise mechanism whereby CXCL12 stabilizes CXCR4’s active state(s), and the complexity of the downstream functional consequences of receptor activation.
|Advisor:||Handel, Tracy M., Trejo, JoAnn|
|Commitee:||Farquhar, Marilyn, Joiner, William, Komives, Elizabeth|
|School:||University of California, San Diego|
|School Location:||United States -- California|
|Source:||DAI-B 79/04(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Pharmacology, Pharmaceutical sciences|
|Keywords:||Chemokine receptors, Chemokines, G protein-coupled receptors|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be