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Identification by Hydrogen/Deuterium Exchange of Structural Changes in Tyrosine Hydroxylase Associated with Regulation

机译：通过氢/氘交换鉴定酪氨酸羟化酶与调控相关的结构变化

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ABSTRACT: The activity of tyrosine hydroxylase is regulated by reversible phosphorylation of serine residues innan N-terminal regulatory domain and catecholamine inhibition at the active site. Catecholamines such asndopamine bind very tightly to the resting enzyme; phosphorylation of Ser40 decreases the affinity forncatecholamines by 3 orders of magnitude. The effects of dopamine binding and phosphorylation of Ser40non the kinetics of deuterium incorporation into peptide bonds were examined by mass spectrometry.nWhen dopamine is bound, three peptic peptides show significantly slower deuterium incorporation, 35-41nand 42-71 in the regulatory domain and 295-299 in the catalytic domain. In the phosphorylated enzyme,npeptide 295-299 shows more rapid incorporation of deuterium, while 35-41 and 42-71 can not be detected.nThese results are consistent with tyrosine hydroxylase existing in two different conformations. In thenclosed conformation, the regulatory domain lies across the active site loop containing residues 295-298;nthis is stabilized when dopamine is bound in the active site. In the open conformation, the regulatoryndomain has moved out of the active site, allowing substrate access; this conformation is favored bynphosphorylation of Ser40.
机译：摘要：酪氨酸羟化酶的活性受N端调控域丝氨酸残基的可逆磷酸化和活性部位的儿茶酚胺抑制作用所调节。儿茶酚胺如天冬胺非常紧密地结合到静止的酶上。 Ser40的磷酸化使亲和儿茶酚胺降低了3个数量级。通过质谱法研究了多巴胺结合和Ser40磷酸化的影响，以及氘掺入肽键的动力学。n当多巴胺结合时，三种消化性肽的掺入速度显着减慢，调节域中35-41n和42-71，295-295n。在催化范围内为299。在磷酸化酶中，肽295-299显示出氘的掺入更快，而35-41和42-71不能被检测到。n这些结果与存在于两种不同构象中的酪氨酸羟化酶一致。在随后的封闭构象中，调节结构域位于包含残基295-298的活性位点环上；当多巴胺结合在活性位点时，这是稳定的。在开放构象中，调节域已移出活性位点，从而允许底物进入。 Ser40的磷酸化有利于这种构象。

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