把“锌”送到需要的地方!Cell:科学家确定首个锌“伴侣蛋白”,开辟全新生物学领域

2022-05-21 生物技术网 生物技术网

锌(Zn)是一种重要的微量营养素。既然是微量,就意味着仅需摄入少量就可以让锌发挥功能。锌是人体第二丰富的过渡金属,仅次于铁。

梅斯点评:也许锰等其它金属离子,尤其是扮演关键角色的离子,在体内应该都有类似的伴侣蛋白,才能将这些离子精准送到相应的器官,以及结合特定的酶,发挥其功能。象锰,锌在免疫系统中发挥重要作用,锂在精神疾病中有重要作用,都值得深入研究。

锌(Zn)是一种重要的微量营养素。既然是微量,就意味着仅需摄入少量就可以让锌发挥功能。锌是人体第二丰富的过渡金属,仅次于铁。但由于不能由机体自然产生,所以锌是一种必需金属元素。我们需要通过食物或补充剂定期摄取,以支持体内依赖锌的生物过程。

在摄入食物后,锌会被体细胞吸收。在每个细胞内,锌与蛋白质结合以支持其结构并发挥功能。据估计,高达10%的蛋白质需要锌才能正常发挥功能。从这个意义上讲,没有锌的锌结合蛋白就像是一辆没有发动机或没用螺丝固定好的汽车,它要么“寸步难行”,要么“瞬间散架”。

因此,锌缺乏与人类疾病密切相关,包括生长缺陷、免疫缺陷、神经紊乱,甚至是癌症。然而不幸的是,世界上超过17%的人口面临缺锌的风险,而且缺锌是发展中国家第五大死亡风险因素,影响到世界近一半人口。

尽管锌对人体健康非常重要,但作为金属,锌如何在细胞内分布?在锌缺乏的情况下,细胞中哪些蛋白质会优先得到锌?锌又如何与这些重要的蛋白质结合?这一系列问题在之前还一直没有答案。

2022年5月17日,发表在《Cell》上的一项新研究中,来自美国范德堡大学和印第安纳大学的研究团队揭开了上述所有问题的答案,并首次确定了锌金属“伴侣蛋白”及其作用机制,同时阐明了锌缺乏对健康的重要影响。该研究为探索一个全新的生物学领域打开了大门。

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已知细胞锌的水平与三磷酸腺苷(ATP)等主要代谢物相似,但细胞内的大部分锌与需要锌的金属蛋白和锌储存蛋白有关,这导致了可用锌的水平极低。在锌限制期间,关键金属蛋白的金属化被认为需要锌的优先分级分配来确保其功能。与铜等其他金属类似,锌向靶金属蛋白的转移被认为是由称为金属伴侣的特殊蛋白质介导的。然而迄今为止,科学家们还未发现此类蛋白质,使金属元素的生物学领域一直存在着巨大的空白。

在这项新研究中,研究人员首先研究了一个保守的脊椎动物蛋白质家族。这是一种选择性地将金属(如锌和铁)插入其他蛋白质的蛋白质。研究人员将这个蛋白家族命名为ZNG1(Zinc regulated GTPase metalloprotein activator 1,锌调节GTP酶金属蛋白激活剂1)。事实证明,所有脊椎动物都有指导细胞产生ZNG1的基因。虽然ZNG1与几种锌结合蛋白相互作用,但其中一种名为METAP1

的蛋白质引起了研究人员的注意。已知METAP1可以激活细胞内许多其他重要的蛋白质;而且,没有功能性METAP蛋白的细胞是无法存活的。

研究人员解释道,之所以对METAP1感兴趣,是因为它与ZNG1蛋白在包括酵母、斑马鱼、小鼠和人类在内的跨物种间的相互作用。

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这一发现表明,ZNG1-METAP1这两种蛋白质之间的联系在4亿年的进化过程中一直保持着。这意味着ZNG1在METAP1功能中的支持作用在所有产生这些蛋白质的生物体中都非常重要。

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为了研究ZNG1在动物健康中的作用,研究人员敲除了小鼠和斑马鱼中编码ZNG1的基因。当缺乏ZNG1的动物被剥夺锌时,它们表现出或无法生长,或发育缺陷(见下图)。尽管这些动物体内仍有微量的锌,但显然,它们已无法让锌发挥作用。这证实了ZNG1有助于METAP1正常工作。

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通过分子成像和其他方法,研究人员还观察到缺乏锌的小鼠细胞中产生能量的线粒体没有正常运作的ZNG1蛋白。这凸显了ZNG1在锌缺乏期间的重要性,它可以帮助细胞将这种微量必需金属分配给线粒体,并最终维持细胞的能量生产。

总之,这项研究不仅阐明了ZNG1和金属蛋白METAP1之间存在明显的物理相互作用,还提供了ZNG1如何与其他靶蛋白相互作用的结构见解。这些发现揭示了一种进化保守策略,以确保在严重缺锌的情况下,锌会被有针对性地分配给最高优先级的蛋白质网络中。

研究人员表示,这项研究只是更好地了解锌金属伴侣在锌水平低时如何维持健康和细胞功能的第一步。但这些发现为了解细胞在营养不良或缺锌时如何利用锌的机制铺平了道路。

进一步研究可以帮助识别维持生命最关键的细胞过程,同时又有助于解决锌缺乏对健康造成的负面影响。

原始出处:

Weiss A, Murdoch CC, Edmonds KA, Jordan MR, Monteith AJ, Perera YR, Rodríguez Nassif AM, Petoletti AM, Beavers WN, Munneke MJ, Drury SL, Krystofiak ES, Thalluri K, Wu H, Kruse ARS, DiMarchi RD, Caprioli RM, Spraggins JM, Chazin WJ, Giedroc DP, Skaar EP.Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis.Cell. 2022 May 13:S0092-8674(22)00458-5. doi: 10.1016/j.cell.2022.04.011.

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    2022-06-07 维他命
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    2022-08-20 小小医者

    #锌##伴侣蛋白#,这是最大的发现!#微量元素#

    0

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    2022-05-21 病毒猎手

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