The dopamine D(4) receptor, the ultimate disordered protein

Abstract

The human D4 dopamine receptor is a synaptic neurotransmitter receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its structure makes it a very unusual and interesting G protein-coupled receptor (GPCR) as it has several polymorphic variants of its gene in the region encoding the third intracellular loop (IL3). This region contains from two to seven or more similar 48 base pair repeats. These repeats cause this protein to have a very high disorder index and this, in turn, makes it very interactive with other proteins. Among GPCRs in general, the unusually proline-rich IL3 is unique to the D4 receptor (D4R). We believe that, as in the D2R, this region of the receptor plays a role in it's interaction with other receptors.

Figure 1

(A) Location of Arg-rich epitope. (B) AKAP anchoring kinases and phosphatases.

Figure 2

Mass spectrum showing the non-covalent complex formed between the phosphorylated and non-phosphorylated the epitopes of the D4R and A2AR.

Figure 3

T model of the D4,4 repeats (A) third intracellular loop (IL3) has more α-helices than the D4,7 repeats-IL3 (B).

Figure 4

Shows graphs of the disorder index of the D2, D3 and D4 (four and seven repeat) third intracellular loop The D4-7 is twice as disordered as the D2 or D3, therefore it is more interactive.