The glucagon-like peptide-1 receptor is a class B G protein coupled receptor (GPCR) that plays key roles in glucose metabolism and is a major therapeutic target for diabetes. The classic two-domain model for class B GPCR activation proposes that the apo-state receptor is auto-inhibited by its extracellular domain, which physically interacts with the transmembrane domain. The binding of the C-terminus of the peptide hormone to the extracellular domain allows the N-terminus of the hormone to insert into the transmembrane domain to induce receptor activation. In contrast to this model, here we demonstrate that glucagon-like peptide-1 receptor can be activated by N-terminally truncated glucagon-like peptide-1 or exendin-4 when fused to the receptor, raising the question regarding the role of N-terminal residues of peptide hormone in glucagon-like peptide-1 receptor activation. Mutations of cysteine 347 to lysine or arginine in intracellular loop 3 transform the receptor into a G protein-biased receptor and allow it to be activated by a nonspecific five-residue linker that is completely devoid of exendin-4 or glucagon-like peptide-1 sequence but still requires the presence of an intact extracellular domain. Moreover, the extracellular domain can activate the receptor in trans in the presence of an intact peptide hormone, and specific mutations in three extracellular loops abolished this extracellular domain trans-activation. Together, our data reveal a dominant role of the extracellular domain in glucagon-like peptide-1 receptor activation and support an intrinsic agonist model of the extracellular domain, in which peptide binding switches the receptor from the auto-inhibited state to the auto-activated state by releasing the intrinsic agonist activity of the extracellular domain.

中文翻译：

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一种通过其胞外域激活胰高血糖素样肽-1受体的内在激动剂机制。

胰高血糖素样肽-1受体是BG类蛋白偶联受体（GPCR），在葡萄糖代谢中起关键作用，是糖尿病的主要治疗靶标。B类GPCR激活的经典两结构域模型提出，脱辅基态受体被其胞外结构域自动抑制，而胞外结构域与跨膜结构域发生物理相互作用。肽激素的C末端与细胞外结构域的结合使激素的N末端插入跨膜结构域以诱导受体激活。与该模型相比，这里我们证明胰高血糖素样肽1受体与受体融合后可以被N末端截短的胰高血糖素样肽1或exendin-4激活，提出了关于肽激素的N-末端残基在胰高血糖素样肽-1受体激活中的作用的问题。在细胞内环3中将半胱氨酸347突变为赖氨酸或精氨酸使该受体转变为G蛋白偏置的受体，并使其被完全不含exendin-4或胰高血糖素样肽1的非特异性五残基接头激活。序列，但仍需要完整的细胞外结构域的存在。此外，胞外域可以在完整的肽激素存在下反式激活受体，并且三个胞外环中的特定突变消除了这种胞外域的反式激活。一起，