Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
IUBMB Life. 2011 Jul;63(7):463-72. doi: 10.1002/iub.473.
It is proposed that the moonlighting concept can be applied to G protein coupled receptors (GPCRs) as, obviously, they can carry out different types of functions. The same motifs in, for example, the third intracellular loop, can moonlight by switching between receptor-receptor interactions and interactions with signaling proteins such as G proteins or calmodulin. A "guide-and-clasp" manner of receptor-receptor interactions has been proposed where the "adhesive guides" may be the triplet homologies. As an example, the triplets AAR (or RAA) and AAE (or EAA) homologies in A(2A) R-D2 R heteromers may guide-and-clasp binding not only of the two protomers but also of calmodulin and G(i) . A beautiful moonlighting phenomenon in the A(2A) R-D2 R heteromer is that the positively charged D2 R N-terminal third intracellular loop epitope (VLRRRRKRVN) may switch between bindings to the negatively charged A(2A) R epitope (SAQEpSQGNT), localized in the medium segment of the C terminus of the A2A receptor to several negative epitopes of calmodulin. Furthermore, overlapping motifs may favor moonlighting to G(i/o) via inter alia electrostatic interaction between triplets AAR(in D2 R third intracellular loop) and AAE (G(i/alpha1) ) (and/or their symmetric variants) contributing to guide-and-clasp D2 R-G(i) interactions Thus, moonlighting in GPCR heteromers can take place via allosteric receptor-receptor interactions and is also described in D1 R-D2 R, D2 R-5-HT2 R,and A1 R-P2Y1 heteromers. Allosteric receptor-receptor interactions in GPCR-receptor tyrosine kinases (RTKs) heteromers and postulated ion channel receptor-RTK heteromers-like, for example, AMPA-NMDA-TrkB heteromers may lead to moonlighting of the participating GPCR and RTK protomers altering, for example, the pattern of the five major signaling pathways of the RTKs favoring MAPK and/or mTOR signaling with high relevance for neurodegenerative processes and depression induced atrophy of neurons. Moonlighting may also develop in the intracellular loops and C-terminal of the GPCRs as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptor.
有人提出，月光蛋白的概念可以应用于 G 蛋白偶联受体（GPCR），因为显然它们可以执行不同类型的功能。例如，在第三细胞内环中相同的基序可以通过在受体-受体相互作用和与 G 蛋白或钙调蛋白等信号蛋白的相互作用之间切换来月光蛋白。已经提出了一种“引导和扣合”受体-受体相互作用方式，其中“粘性引导”可能是三联体同源性。例如，A2A 受体-D2R 异源二聚体中的 AAR（或 RAA）和 AAE（或 EAA）同源性三联体可能引导和扣合不仅结合两个前体，还结合钙调蛋白和 G(i)。A2A 受体-D2R 异源二聚体中的一个美丽的月光蛋白现象是，带正电荷的 D2R N 端第三细胞内环表位（VLRRRRKRVN）可以在与 A2A 受体中带负电荷的表位（SAQEpSQGNT）之间切换，该表位定位于 A2A 受体的 C 端中片段到钙调蛋白的几个负表位。此外，重叠基序可能通过 D2R 第三细胞内环中的三联体 AAR（和 G(i/alpha1) 中的 AAE）之间的静电相互作用等有利于与 G(i/o)的月光蛋白，有助于引导和扣合 D2R-G(i)相互作用。因此，GPCR 异源二聚体中的月光蛋白可以通过变构受体-受体相互作用发生，也在 D1R-D2R、D2R-5-HT2R 和 A1R-P2Y1 异源二聚体中描述。GPCR-受体酪氨酸激酶（RTK）异源二聚体中的变构受体-受体相互作用和假设的离子通道受体-RTK 异源二聚体，例如 AMPA-NMDA-TrkB 异源二聚体，可能导致参与的 GPCR 和 RTK 前体的月光蛋白，改变例如 RTKs 的五种主要信号通路的模式，有利于 MAPK 和/或 mTOR 信号，这与神经退行性过程和神经元诱导的萎缩高度相关。由于不同类型的 G 蛋白和受体相互作用蛋白在受体的这些结构域之间的动态变构相互作用，月光蛋白也可能在 GPCR 的细胞内环和 C 端中发展。
