CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices
CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices
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DOI：
10.1038/nsmb1278
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发表时间：
2007-08-01
影响因子：
16.8
通讯作者：
Forman-Kay, Julie D.
中科院分区：
文献类型：
--
作者：
Baker, Jennifer M. R.;Hudson, Rhea P.;Forman-Kay, Julie D.
囊性纤维化跨膜电导调节器(CFTR)的调节(R)区域本质上是无序的，必须在多个位置被磷酸化才能完全激活CFTR通道，而不需要一个特定的磷酸化位点。此外，cftr的核苷酸结合域(NBD)上的核苷酸结合和水解是通道门控所必需的。我们报告了在没有和存在NBD1的情况下的核磁共振研究，这些研究提供了分离的R区的结构细节以及它与NBD1在残基水平上的相互作用。在R区有几个测得的分数螺旋倾向的位置与NBD1相互作用。磷酸化降低了许多R区位点的螺旋度，并减少了它们之间的NBD1相互作用。这一证据表明，NBD1与动态复合体瞬时结合了R区的不同位点，这一证据为CFTR活性依赖于多个PKA磷酸化位点提供了结构上的解释。
The regulatory (R) region of the cystic fibrosis transmembrane conductance regulator (CFTR) is intrinsically disordered and must be phosphorylated at multiple sites for full CFTR channel activity, with no one specific phosphorylation site required. In addition, nucleotide binding and hydrolysis at the nucleotide-binding domains (NBDs) of CFTR are required for channel gating. We report NMR studies in the absence and presence of NBD1 that provide structural details for the isolated R region and its interaction with NBD1 at residue-level resolution. Several sites in the R region with measured fractional helical propensity mediate interactions with NBD1. Phosphorylation reduces the helicity of many R-region sites and reduces their NBD1 interactions. This evidence for a dynamic complex with NBD1 that transiently engages different sites of the R region suggests a structural explanation for the dependence of CFTR activity on multiple PKA phosphorylation sites.