Investigation of Allosteric Transitions Induced by Oligomerization and Mutations in Protein Molecules

The concept of receptor oligomerization has been a hotly debated subjected amongst the GPCR field. Identification of receptor oligomers has been confirmed for a number of GPCR's but the exact mechanism and effects of this oligomerization is still not well understood. CXCR4 is a vital chemokine receptor that is involved in a plethora of bodily functions and disease models. The oligomerization of CXCR4 has been connected with the development of tolerance to FDA approved drug, AMD3100. By using novel engineered CXCR4 constructs, we have identified key functions of CXCR4 oligomerization. An initial discovery was confirmation of a ligand-independent receptor activation mechanism related to receptor oligomerization. We believe this ligand-independent mechanism is associated with CXCR4 structural changes, these changes are associated with a decrease in conformational dynamics of the receptor and orientation of ECL2, a key motif in ligand binding. Furthermore, a potentially novel mechanism of receptor post-translational modification has been observed, with increasing oligomerization changing the glycosylation patterns of CXCR4. Oligomerization of CXCR4 can be coupled with a number of effects on not just receptor structure but also changes key receptor functions.