Structure-function relationships in the neuropeptide S receptor - Molecular consequences of the asthma-associated mutation N107I
Structure-function relationships in the neuropeptide S receptor - Molecular consequences of the asthma-associated mutation N107I
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DOI：
10.1074/jbc.m603691200
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发表时间：
2006-08-25
影响因子：
4.8
通讯作者：
Therien, Alex G.
中科院分区：
文献类型：
--
作者：
Bernier, Virginie;Stocco, Rino;Therien, Alex G.
神经肽S（Neuropeptide S，NPSR）及其受体（NPSR）被认为在哮喘发病机制中起作用; NPSR内的许多单核苷酸多态性已被证明与哮喘发病率增加相关。一个这样的单核苷酸多态性导致错义突变N107 I，其导致NPSR的NP 107效力增加。为了深入了解结构与功能的关系，在NPSR和NPSR，我们首先进行了有限的结构表征的NPSR和肽进行了广泛的诱变研究。我们的研究结果表明，NPSR的NH 2-末端三分之一，特别是残基Phe-2，Arg-3，Asn-4和瓦尔-6，是激活NPSR所必需和充分的。此外，肽内新生螺旋的一部分，跨越残基5至13，作为抑制受体活化的调节区。值得注意的是，这种抑制在哮喘相关的NPSR的N107 I变体中不存在，这表明残基107与前述的NPSR调节区相互作用。虽然这种相互作用可能是与N107 I变体相关的效力增加的根源，但我们在这里表明，突变也会导致突变受体的细胞表面表达增加，从而导致Emax的最大效力（Emax）随之增加。我们的研究结果确定了参与NPSR激活的N107 I的关键残基，并为N107 I突变的功能效应及其与哮喘的假定病理生理学联系提供了分子基础。
Neuropeptide S (NPS) and its receptor (NPSR) are thought to have a role in asthma pathogenesis; a number of single nucleotide polymorphisms within NPSR have been shown to be associated with an increased prevalance of asthma. One such single nucleotide polymorphism leads to the missense mutation N107I, which results in an increase in the potency of NPS for NPSR. To gain insight into structure-function relationships within NPS and NPSR, we first carried out a limited structural characterization of NPS and subjected the peptide to extensive mutagenesis studies. Our results show that the NH2-terminal third of NPS, in particular residues Phe-2, Arg-3, Asn-4, and Val-6, are necessary and sufficient for activation of NPSR. Furthermore, part of a nascent helix within the peptide, spanning residues 5 through 13, acts as a regulatory region that inhibits receptor activation. Notably, this inhibition is absent in the asthma-linked N107I variant of NPSR, suggesting that residue 107 interacts with the aforementioned regulatory region of NPS. Whereas this interaction may be at the root of the increase in potency associated with the N107I variant, we show here that the mutation also causes an increase in cell-surface expression of the mutant receptor, leading to a concomitant increase in the maximal efficacy (Emax) of NPS. Our results identify the key residues of NPS involved in NPSR activation and suggest a molecular basis for the functional effects of the N107I mutation and for its putative pathophysiological link with asthma.