Receptor dimerization

CCR5 CCR5 Co-IP, BRET, FRET/FLIM Constitutive 

Synergized signaling, additional G protein coupling Negative binding cooperativity (chemokines and small molecule antagonists) 

Transinhibition of chemokine-induced Ca mobilization and migration Delayed HIV progression 

Ligand and antibody-induced dimerization decreases HIV infection 

Translocation to immunological synaps during T cell activation 

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FIGURE 3.3 Displacement of prebound radioligand [A ] by non-radioactive concentrations of [A]. Curve for a= 1 denotes no cooperativity in binding (i.e., formation of the receptor dimer does not lead to a change in the affinity of the receptor for either [A] or [A ]). The curve a= 10 indicates a system whereby formation of the receptor dimer leads to a tenfold increase in the affinity for both [A ] and [A], In this case, it can be seen that addition on the nonradioactive ligand [A] actually leads to an increase in the amount of radioligand [A ] bound before a decrease at higher concentrations of [A], For this simulation [A ]/Kd = 0.1. 

Radioligand binding to receptor dimers demonstrating co-operative behavior (3.13.1)... 

Radioligand Binding to Receptor Dimers Demonstrating Cooperative Behavior... 

It is assumed that receptor dimers can form in the cell membrane (two [R] species to form one [R-R] species). Radioligand [A ] can bind to the receptor [R] to form radioactive complexes [A R], [A R — AR], and [A R — A R], It is also assumed that there is an allosteric interaction between... 

For proteins such as tyrosine-kinase receptors, dimerization (the association of two receptors to form a new species... 

Table 9.2b). Increasing also is the list of phenotypes associated with these dimerization processes. With the emergence of receptor dimers as possible therapeutic targets have come parallel ideas with dimerized ligands (see Section 9.5). 

Biological targets may consist of single-entity proteins, complexes of receptors (dimers), or receptors plus accessory proteins. Mixtures of gene products can produce unique phenotypic biological targets. 

AbdAlla, S., Lother, H., el Massiery, A., and Quitterer, U. (2001). Increased AT(1) receptor dimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nature Med. 7 1003-1009. 

Terrillon S, Bouvier M (2004) Roles of G-protein-coupled receptor dimerization. EMBO Rep 5 30-34... 

Toth PT, Ren D, Miller RJ (2004) Regulation of CXCR4 receptor dimerization by the chemokine SDF-lalpha and the HIV-1 coat protein gpl20 a fluorescence resonance energy transfer (FRET) study. J Pharmacol Exp Ther 310 8-17 Tran PB, Miller RJ (2005) HIV-1, chemokines and neurogenesis. Neurotox Res 8 149-158 Tran PB, Ren D, Veldhouse TJ, Miller RJ (2004) Chemokine receptors are expressed widely by embryonic and adult neural progenitor cells. J Neurosci Res 76 20-34... 

Hemanz-Falcon P, Rodriguez-Frade JM, Serrano A, et al. Identification of amino acid residues crucial for chemokine receptor dimerization. Nat Immunol 2004 5(2) 216-223. 

Mellado M, Rodriguez-Frade JM, Manes S, Martinez AC. Chemokine signaling and functional responses the role of receptor dimerization and TK pathway activation. Annu Rev Immunol 2001 19 397 121. 

Vila-Coro AJ, Mellado M, Martin de Ana A, et al. HIV-1 infection through the CCR5 receptor is blocked by receptor dimerization. Proc Natl Acad Sci U S A 2000 97(7) 3388-3393. 

Toth PT, Ren D, Miller RJ. Regulation of CXCR4 receptor dimerization by the chemokine SDF-lalpha and the HIV-1 coat protein gpl20 a fluorescence resonance energy transfer (FRET) study. J Pharmacol Exp Ther 2004 310(1) 8-17. 

Vila-Coro AJ, Rodriguez-Frade JM, Martin De Ana A, Moreno-Ortiz MC, Martinez AC, Mellado M. The chemokine SDF-lalpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J 1999 13(13) 1699-1710. 

Milligan G, Wilson S, Lopez-Gimenez JF. The specificity and molecular basis of alphal-adrenoceptor and CXCR chemokine receptor dimerization. J Mol Neurosci 2005 26 161-168. 

The crystal structures of monomeric ligands such as GH and EPO in complex with their respective receptors show that these hormones are bivalent and one ligand binds simultaneously to two receptor molecules to form a 1 2 (ligand receptor) complex. Receptor dimerization is further stabilized by additional receptor-receptor interactions. 

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