Department of Medical Neurobiology, Institute for Medical Research-Israel-Canada, Hebrew University, Hadassah Medical School, Jerusalem 91120, Israel.
Biochemistry. 2009 Dec 29;48(51):12329-36. doi: 10.1021/bi901234a.
RIC-3 belongs to a conserved family of proteins influencing maturation of nicotinic acetylcholine receptors (nAChRs). RIC-3 homologues were shown to differently affect different nAChRs. Here we show that coexpression with RIC-3 increases the level of surface expression of DEG-3 while slightly reducing the level of surface expression of DES-2, both subunits of the DEG-3/DES-2 nAChRs. Those different effects are a likely explanation for the previously demonstrated effects of RIC-3, an endoplasmic reticulum resident protein, on properties of this receptor. To understand how RIC-3 interacts with different nAChR subunits, we identified and characterized domains and residues enabling this interaction. This analysis shows that conserved residues in the second RIC-3 transmembrane domain are needed for its interactions with two different Caenorhabditis elegans nAChRs, DEG-3/DES-2 and ACR-16. These conserved residues do not, however, function alone; rather, we show that additional domains also enable RIC-3's interactions with these receptors. Interestingly, the relative importance of these residues or of other domains mediating interactions of RIC-3 with nAChRs differs for the two different receptors. Differences in the way that RIC-3, predicted to be an intrinsically disordered protein, interacts with different receptors and receptor subunits suggest that it may adopt different conformations to enable these interactions. Such differences may explain both the effects of RIC-3 on receptor properties and the differences in its effects on different receptors.
RIC-3 属于影响烟碱型乙酰胆碱受体（nAChRs）成熟的保守蛋白家族。已经表明 RIC-3 同源物以不同的方式影响不同的 nAChRs。在这里，我们表明与 RIC-3 共表达会增加 DEG-3 的表面表达水平，同时略微降低 DES-2 的表面表达水平，DEG-3/DES-2 nAChRs 的两个亚基。这些不同的影响可能是先前证明的内质网驻留蛋白 RIC-3 对该受体特性的影响的一个可能解释。为了了解 RIC-3 如何与不同的 nAChR 亚基相互作用，我们鉴定并表征了使这种相互作用能够发生的结构域和残基。该分析表明，第二 RIC-3 跨膜结构域中的保守残基对于其与两种不同的秀丽隐杆线虫 nAChRs（DEG-3/DES-2 和 ACR-16）的相互作用是必需的。然而，这些保守残基不能单独发挥作用；相反，我们表明，其他结构域也能够使 RIC-3 与这些受体相互作用。有趣的是，对于这两个不同的受体，介导 RIC-3 与 nAChRs 相互作用的这些残基或其他结构域的相对重要性不同。RIC-3 以不同的方式与不同的受体和受体亚基相互作用，这表明它可能采用不同的构象来实现这些相互作用。这种差异可能解释了 RIC-3 对受体特性的影响以及它对不同受体的影响的差异。
