Dissertation/Thesis Abstract

The author has requested that access to this graduate work be delayed until 2019-12-21. After this date, this graduate work will be available on an open access basis.
Understanding CXC Chemokine Receptor 4 Activation by CXC Chemokine Ligand 12
by Stephens, Bryan S., Ph.D., University of California, San Diego, 2017, 199; 10686706
Abstract (Summary)

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.

Indexing (document details)
Advisor: Handel, Tracy M., Trejo, JoAnn
Commitee: Farquhar, Marilyn, Joiner, William, Komives, Elizabeth
School: University of California, San Diego
Department: Biomedical Sciences
School Location: United States -- California
Source: DAI-B 79/04(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Cellular biology, Pharmacology, Pharmaceutical sciences
Keywords: Chemokine receptors, Chemokines, G protein-coupled receptors
Publication Number: 10686706
ISBN: 9780355545333
Copyright © 2019 ProQuest LLC. All rights reserved. Terms and Conditions Privacy Policy Cookie Policy
ProQuest