Many of us are familiar with mad cow disease–the neurodegenerative disease caused by prions. Although they have a similar name, the less familiar prion-like domains (PLDs) refer to something different–unique, low-complexity regions of proteins that are capable of regulating gene expression and affecting important cellular processes.
我們之中很多人熟知瘋牛症，這是一種由普里昂蛋白引發的神經退化性疾病。雖然此些蛋白具有相似的名稱，不過較少熟知之類普里昂蛋白的結構域(PLDs)，指的是不同的東西。也就是，蛋白質能調節基因表現，及影響重要細胞變化過程之獨特、低複雜性的區域。
Prion-like domains have become a topic of interest because of their connection with a variety of debilitating brain diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In fact, mutations in PLDs of some genes have been shown to cause neurodegenerative disease. For example, mutations in PLDs of the genes hnRNPA2B1 and hnRNPA1 can cause the neurodegenerative disorders ALS and multisystem proteinopathy.
類普里昂蛋白的結構域已經成為，一項令人感興趣的主題。因為，它們與諸如肌萎縮側索硬化(ALS)等，各種使人衰弱之腦部疾病及額顳葉癡呆症的關聯性。實際上，在某些基因之PLDs中的突變體已經被證實，導致神經退化性疾病。譬如，在hnRNPA2B1及hnRNPA1基因之PLDs中的突變體，會引發ALS及多系統蛋白病等，神經退化性疾病。
A recent study using data obtained at the U.S. Department of Energy’s Advanced Photon Source (APS) completed a comprehensive biophysical investigation of PLDs in the protein hnRNPA1 to uncover the major behavioral and structural features of these domains. This meaningful work, published in the journal Science, may lead to discoveries that can help individuals living with such neurodegenerative diseases.
一項最近使用獲自美國能源部所屬先進光子源(APS)數據的研究完成了，有關在hnRNPA1蛋白中，PLDs之廣泛生物物理的調查研究，來揭露此些結構域的主要作用及結構特徵。該項發表於《科學》期刊，富有意義的研究，可能引領出諸多能有助於，罹患此類神經退化性疾病之個體生活的發現。
Amyotrophic lateral sclerosis is a devastating disease of the nervous system that affects the brain and spinal cord. Patients often present with symptoms such as slurred speech, muscle twitching, and muscle weakness. Patients lose total control of muscle function as the disease progresses, resulting in a fatal inability to perform everyday tasks such as eating, breathing, moving, and speaking. Age of onset tends to occur later in adult life; at present, there is no cure.
肌萎縮側索硬化是一種，會影響大腦及脊髓之神經系統的毀滅性疾病。患者經常出現諸如，語言含糊不清、肌肉抽搐及肌肉無力等症狀。隨著該種疾病的發展，患者喪失對肌肉功能的完全控制，導致一種致命的無法執行，諸如進食、呼吸、活動及說話等日常事情。發病年齡傾向發生於成年後。目前，沒有治療法。
Although the cause of ALS is largely unknown, genetic mutations in PLDs is known to be involved. PLDs have been shown to impact a variety of important cellular processes, such as cell division and understanding how cells respond to stress. The proteins hnRNPA2B1 and hnRNPA1 serve important functions in the processing and stabilization of mRNA. More broadly, PLDs can drive the aggregation of proteins within cells.
雖然ALS的原因大半不詳，不過已知涉及於PLDs的遺傳突變。PLDs已經被證實，影響了諸如細胞分裂及瞭解細胞如何對壓力作出反應等，各種重要細胞變化過程。hnRNPA2B1及hnRNPA1蛋白質促進了，在信使RNA(mRNA)之處理及穩定上的諸多重要功能。更廣泛地說，PLDs能驅動細胞內蛋白質的聚合。
Since PLDs have such a palpable relevance to medicine and brain health, investigations into their behavior and structure are highly valuable. Seeking to better understand how PLDs behave and affect molecular aggregation, the authors in this study, from St. Jude Children’s Research Hospital, Washington University in St. Louis, and Washington University School of Medicine, found that the temperature-dependent compaction of molecules within a liquid solution is determined by the number of aromatic residues in PLDs.
由於PLDs具有與醫學及腦部健康如此明顯的關聯性，因此調查研究其作用及結構是非常重要的。在該項研究中，尋求更深入瞭解PLD如何起作用及影響分子聚合，來自美國聖路易斯市華盛頓大學，聖裘德兒童研究醫院，及華盛頓大學醫學院的撰文者們發現，在液體溶液中，分子取決於溫度的壓實，是由PLDs中芳香族殘基的數量所決定。
The uniform patterning of these aromatic residues promotes a phenomenon known as liquid-liquid phase separation while preventing aggregation. Liquid-liquid phase separation is a physical process that leads to the formation of two co-existing liquid phases (a dilute and a dense phase), which is the underlying process for the formation of many non-membrane bound cellular compartments.
這些芳香族殘基的均勻形成圖案促進了一種，被稱為液-液相分離的現象，同時阻止了聚合。液-液相分離是一種，導致形成(稀釋相及緻密相)兩個共存液相的物理過程。這是形成諸多非膜束縛細胞室的基本過程。
The authors additionally put forth an impressive stickers-and-spacers model (adapted from the associative polymer field) that can be used to make predictions regarding the behavior of PLDs. This study utilized multiscale simulations, nuclear magnetic resonance spectroscopy, and small-angle x-ray scattering (SAXS) to uncover behavioral and structural features of PLDs (Fig. 1).
此些撰文者們另外提出一種，能被用來作出諸多有關PLDs之作用預測，令人印象深刻的粘貼物與間隔物模型(改編自締合聚合物領域）。這項研究利用了多尺度模擬、核磁共振光譜技術及小角度X-射線散射(SAXS)，來揭露PLDs的作用及結構特徵。
The SAXS research was carried out using high-brightness x-rays at the Biophysics Collaborative Access Team 18-ID beamline at the APS (the APS is an Office of Science user facility at Argonne National Laboratory). The high brightness x-rays were essential to characterize small differences between structural features of different mutants of the PLD.
上述SAXS研究是使用，先進光子源(美國能源部科學局位於阿爾岡國家實驗室的用戶設備)之生物物理協作存取團隊18-ID光束線進行的。該高度明亮的X射線是顯現，PLD不同突變體結構特徵間，微小差異所不可或缺的。
The data generated from this work will enable more precise characterization of PLDs within cells, which will in turn provide the ability to predict how PLDs form and dissolve condensates in response to different circumstances (e.g., protein concentration, conditions in cells).
這些從該項研究產生的數據，將使能更精確描述細胞內PLDs特徵，依序將提供預測，在對不同狀況(譬如，蛋白質濃度、細胞中的情況)作出反應時，PLD如何形成及溶解冷凝物的能力。
Given that PLDs appear to have an important role in the maintenance of brain health, the significant insights into how phase behavior and structure of PLDs are coupled may allow for the development of PLD-targeted therapeutics that can help patients with ALS and other debilitating neurodegenerative disorders.
鑒於PLDs在維持腦部健康上，似乎具有一種重要角色。此些有關PLDs之相行為(描述相互接觸的物質，物理上不同可分離部分之間的複雜交互作用)及結構，如何被聯繫在一起的重要洞察力可能為，開發鎖定PLD、能有助於罹患ALS及其他使人衰弱之神經退化性疾病患者的療法，留出餘地。
原文網址：https://www.aps.anl.gov/APS-Science-Highlight/2020-08-10/uncovering-unique-structural-features-in-protein-regions
翻譯：許東榮
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