黑腹果蝇 frataxin:蛋白质晶体和预测溶液结构以及铁结合区域的鉴定。

IF 2.6 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Acta Crystallographica. Section D, Structural Biology Pub Date : 2023-01-01 DOI:10.1107/S2059798322011639
Andria V Rodrigues, Sharon Batelu, Tiara V Hinton, John Rotondo, Lindsey Thompson, Joseph S Brunzelle, Timothy L Stemmler
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引用次数: 1

摘要

弗里德里希共济失调症(FRDA)是一种遗传性心脏变性和神经退行性疾病,每五万美国人中就有一人患病。弗里德里希共济失调症的发病原因是细胞无法产生足够数量的蛋白 frataxin,或者产生了一种无功能形式的蛋白 frataxin,这是一种与线粒体铁硫簇生物合成有关的关键分子。在线粒体铁硫簇(ISC)组装途径中,frataxin 是半胱氨酸脱硫酶的异构调节剂,而半胱氨酸脱硫酶是为[2Fe-2S]簇组装提供硫的酶。frataxin 是一种已知的铁结合蛋白,也与向支架蛋白(负责直接组装 [2Fe-2S] 簇的 ISC 分子)输送亚铁离子有关。本报告的目的是利用 X 射线晶体学和核磁共振(NMR)光谱学提供黑腹果蝇 frataxin 同源物(Dfh)的结构细节,以便为理解该蛋白质的结构-功能相关性提供所需的基础性见解。此外,还利用核磁共振铁(II)滴定法提供了该蛋白质上的金属接触点,以更好地了解它是如何结合铁并将其输送到 ISC 支架蛋白上的。这里还概述了 Dfh 与其同源物在结构和功能上的相似性。结构数据显示,细菌、酵母、人类和果蝇的 frataxins 结构相似,但 Dfh 的 C 端结构可能有助于提高蛋白质的稳定性。Dfh的螺旋1和链1上的铁结合位置在各同源物之间也是一致的。
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Drosophila melanogaster frataxin: protein crystal and predicted solution structure with identification of the iron-binding regions.

Friedreich's ataxia (FRDA) is a hereditary cardiodegenerative and neurodegenerative disease that affects 1 in 50 000 Americans. FRDA arises from either a cellular inability to produce sufficient quantities or the production of a nonfunctional form of the protein frataxin, a key molecule associated with mitochondrial iron-sulfur cluster biosynthesis. Within the mitochondrial iron-sulfur cluster (ISC) assembly pathway, frataxin serves as an allosteric regulator for cysteine desulfurase, the enzyme that provides sulfur for [2Fe-2S] cluster assembly. Frataxin is a known iron-binding protein and is also linked to the delivery of ferrous ions to the scaffold protein, the ISC molecule responsible for the direct assembly of [2Fe-2S] clusters. The goal of this report is to provide structural details of the Drosophila melanogaster frataxin ortholog (Dfh), using both X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, in order to provide the foundational insight needed to understand the structure-function correlation of the protein. Additionally, NMR iron(II) titrations were used to provide metal contacts on the protein to better understand how it binds iron and aids its delivery to the ISC scaffold protein. Here, the structural and functional similarities of Dfh to its orthologs are also outlined. Structural data show that bacterial, yeast, human and Drosophila frataxins are structurally similar, apart from a structured C-terminus in Dfh that is likely to aid in protein stability. The iron-binding location on helix 1 and strand 1 of Dfh is also conserved across orthologs.

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来源期刊
Acta Crystallographica. Section D, Structural Biology
Acta Crystallographica. Section D, Structural Biology BIOCHEMICAL RESEARCH METHODSBIOCHEMISTRY &-BIOCHEMISTRY & MOLECULAR BIOLOGY
CiteScore
4.50
自引率
13.60%
发文量
216
期刊介绍: Acta Crystallographica Section D welcomes the submission of articles covering any aspect of structural biology, with a particular emphasis on the structures of biological macromolecules or the methods used to determine them. Reports on new structures of biological importance may address the smallest macromolecules to the largest complex molecular machines. These structures may have been determined using any structural biology technique including crystallography, NMR, cryoEM and/or other techniques. The key criterion is that such articles must present significant new insights into biological, chemical or medical sciences. The inclusion of complementary data that support the conclusions drawn from the structural studies (such as binding studies, mass spectrometry, enzyme assays, or analysis of mutants or other modified forms of biological macromolecule) is encouraged. Methods articles may include new approaches to any aspect of biological structure determination or structure analysis but will only be accepted where they focus on new methods that are demonstrated to be of general applicability and importance to structural biology. Articles describing particularly difficult problems in structural biology are also welcomed, if the analysis would provide useful insights to others facing similar problems.
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