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首页> 外文期刊>Pigment cell research >A three-dimensional model of mammalian tyrosinase active site accounting for loss of function mutations
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A three-dimensional model of mammalian tyrosinase active site accounting for loss of function mutations

机译：解释功能突变损失的哺乳动物酪氨酸酶活性位点的三维模型

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Tyrosinases are the first and rate-limiting enzymes in the synthesis of melanin pigments responsible for colouring hair, skin and eyes. Mutation of tyrosinases often decreases melanin production resulting in albinism, but the effects are not always understood at the molecular level. Homology modelling of mouse tyrosinase based on recently published crystal structures of non-mammalian tyrosinases provides an active site model accounting for loss-of-function mutations. According to the model, the copper-binding histidines are located in a helix bundle comprising four densely packed helices. A loop containing residues M374, S375 and V377 connects the CuA and CuB centres, with the peptide oxygens of M374 and V377 serving as hydrogen acceptors for the NH-groups of the imidazole rings of the copper-binding His367 and His180. Therefore, this loop is essential for the stability of the active site architecture. A double substitution (MS375)-M-374 ->(374)GG(375) or a single M374G mutation lead to a local perturbation of the protein matrix at the active site affecting the orientation of the H367 side chain, that may be unable to bind CuB reliably, resulting in loss of activity. The model also accounts for loss of function in two naturally occurring albino mutations, S380P and V393F. The hydroxyl group in S380 contributes to the correct orientation of M374, and the substitution of V393 for a bulkier phenylalanine sterically impedes correct side chain packing at the active site. Therefore, our model explains the mechanistic necessity for conservation of not only active site histidines but also adjacent amino acids in tyrosinase.
机译：酪氨酸酶是黑色素色素合成中的第一种酶和限速酶，负责使头发，皮肤和眼睛着色。酪氨酸酶的突变通常会降低黑色素的产生，从而导致白化病，但在分子水平上并不总是了解其作用。基于最近发表的非哺乳动物酪氨酸酶的晶体结构的小鼠酪氨酸酶的同源性建模，提供了一个功能丧失突变的活性位点模型。根据该模型，结合铜的组氨酸位于包含四个密集堆积的螺旋的螺旋束中。包含残基M374，S375和V377的环连接CuA和CuB中心，M374和V377的肽氧充当与铜结合的His367和His180的咪唑环的NH-基团的氢受体。因此，此循环对于活动站点体系结构的稳定性至关重要。双取代（MS375）-M-374->（374）GG（375）或单个M374G突变会导致蛋白质基质在活性位点发生局部扰动，从而影响H367侧链的方向，这可能无法不能可靠地结合CuB，导致活性降低。该模型还说明了两个自然发生的白化突变S380P和V393F的功能丧失。 S380中的羟基有助于M374的正确取向，而V393取代较大的苯丙氨酸在空间上阻碍了活性位点的正确侧链堆积。因此，我们的模型解释了不仅保留活性位点组氨酸，而且保留酪氨酸酶中相邻氨基酸的机制的必要性。

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