An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain.
An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain.
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通过其胞外结构域激活胰高血糖素样肽-1 受体的内在激动剂机制。
DOI：
10.1038/celldisc.2016.42
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发表时间：
2016
期刊：
影响因子：
33.5
通讯作者：
中科院分区：
文献类型：
--
作者：
胰高血糖素样肽-1受体是B类G蛋白偶联受体（GPCR），其在葡萄糖代谢中起关键作用，并且是糖尿病的主要治疗靶点。B类GPCR激活的经典双结构域模型提出脱辅基状态受体被其胞外结构域自动抑制，胞外结构域与跨膜结构域物理相互作用。肽激素的C-末端与细胞外结构域的结合允许激素的N-末端插入跨膜结构域以诱导受体活化。与此模型相反，在这里，我们证明，胰高血糖素样肽-1受体可以被激活的N-末端截短的胰高血糖素样肽-1或exendin-4融合时的受体，提出了关于N-末端残基的肽激素在胰高血糖素样肽-1受体激活的作用的问题。胞内环3中半胱氨酸347突变为赖氨酸或精氨酸将受体转化为G蛋白偏向性受体，并允许其被完全缺乏毒蜥外泌肽-4或胰高血糖素样肽-1序列但仍需要存在完整胞外结构域的非特异性五残基接头激活。此外，细胞外结构域可以激活受体的反式在一个完整的肽激素的存在下，和特定的突变，在三个细胞外环废除这种细胞外结构域的反式激活。总之，我们的数据揭示了胞外结构域在胰高血糖素样肽-1受体激活中的主导作用，并支持胞外结构域的内在激动剂模型，其中肽结合通过释放胞外结构域的内在激动剂活性将受体从自抑制状态切换到自激活状态。
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.
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影响因子：
64.8
作者：
Hollenstein, Kaspar;Kean, James;Marshall, Fiona H.
通讯作者：
Marshall, Fiona H.
影响因子：
4.8
作者：
MontroseRafizadeh, C;Yang, H;Eng, J
通讯作者：
Eng, J
影响因子：
3.6
作者：
Dong, Maoqing;Pinon, Delia I.;Miller, Laurence J.
通讯作者：
Miller, Laurence J.
DOI：
10.1073/pnas.0710487105
发表时间：
2008-01-08
影响因子：
11.1
作者：
Barnea, Gilad;Strapps, Walter;Lee, Kevin J.
通讯作者：
Lee, Kevin J.
影响因子：
3.1
作者：
Dong, Maoqing;Pinon, Delia I.;Miller, Laurence J.
通讯作者：
Miller, Laurence J.