Off-pathway 3D-structure provides protection against spontaneous Asn/Asp isomerization: shielding proteins Achilles heel.

IF 7.2 2区 生物学 Q1 BIOPHYSICS Quarterly Reviews of Biophysics Pub Date : 2020-01-31 DOI:10.1017/S003358351900009X
András Láng, Imre Jákli, Kata Nóra Enyedi, Gábor Mező, Dóra K Menyhárd, András Perczel
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引用次数: 1

Abstract

Spontaneous deamidation prompted backbone isomerization of Asn/Asp residues resulting in - most cases - the insertion of an extra methylene group into the backbone poses a threat to the structural integrity of proteins. Here we present a systematical analysis of how temperature, pH, presence of charged residues, but most importantly backbone conformation and dynamics affect isomerization rates as determined by nuclear magnetic resonance in the case of designed peptide-models. We demonstrate that restricted mobility (such as being part of a secondary structural element) may safeguard against isomerization, but this protective factor is most effective in the case of off-pathway folds which can slow the reaction by several magnitudes compared to their on-pathway counterparts. We show that the geometric descriptors of the initial nucleophilic attack of the isomerization can be used to classify local conformation and contribute to the design of stable protein drugs, antibodies or the assessment of the severity of mutations.

At any –Asn/AspGly– sites in proteins a spontaneous backbone isomerization occurs within days under physiological conditions leading to various forms of proteopathy. This unwanted transformation especially harmful to long-lived proteins (e.g. hemoglobin and crystallins), can be slowed down, though never stopped, by a rigid three-dimensional protein fold, if it can delay in the conformational maze, on-pathway intermediates from occurring.

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非通路3d结构提供了对自发Asn/Asp异构化的保护:屏蔽蛋白质的阿喀琉斯之踵。
自发脱酰胺促进Asn/Asp残基的主链异构化,导致在大多数情况下,在主链中插入一个额外的亚甲基对蛋白质的结构完整性构成威胁。在这里,我们提出了一个系统的分析如何温度,pH值,带电残基的存在,但最重要的是主链构象和动力学影响核磁共振确定的多肽模型的情况下异构化率。我们证明,受限的流动性(如二级结构元件的一部分)可以防止异构化,但这种保护因素在非通路折叠的情况下最有效,与通路上的对偶物相比,它可以将反应减慢几个量级。研究表明,异构化初始亲核攻击的几何描述符可用于局部构象分类,并有助于设计稳定的蛋白质药物,抗体或评估突变的严重程度。在任何- asn /AspGly -位点,在生理条件下,自发的主干异构化在几天内发生,导致各种形式的蛋白质病变。这种不必要的转化对长寿命蛋白质(如血红蛋白和结晶蛋白)尤其有害,如果它能延缓构象迷宫中通路上中间体的发生,则可以通过刚性的三维蛋白质折叠来减缓,尽管永远不会停止。
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来源期刊
Quarterly Reviews of Biophysics
Quarterly Reviews of Biophysics 生物-生物物理
CiteScore
12.90
自引率
1.60%
发文量
16
期刊介绍: Quarterly Reviews of Biophysics covers the field of experimental and computational biophysics. Experimental biophysics span across different physics-based measurements such as optical microscopy, super-resolution imaging, electron microscopy, X-ray and neutron diffraction, spectroscopy, calorimetry, thermodynamics and their integrated uses. Computational biophysics includes theory, simulations, bioinformatics and system analysis. These biophysical methodologies are used to discover the structure, function and physiology of biological systems in varying complexities from cells, organelles, membranes, protein-nucleic acid complexes, molecular machines to molecules. The majority of reviews published are invited from authors who have made significant contributions to the field, who give critical, readable and sometimes controversial accounts of recent progress and problems in their specialty. The journal has long-standing, worldwide reputation, demonstrated by its high ranking in the ISI Science Citation Index, as a forum for general and specialized communication between biophysicists working in different areas. Thematic issues are occasionally published.
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