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Proteopathy | protein conformational diseases | 蛋白质构象疾病


Proteopathy 一词是由Proteo (蛋白质)和pathy(疾病)构成,是指蛋白质构象性疾病,又称为protein conformational diseases。 简单地讲,蛋白质构象病就是指蛋白质三维结构出现错乱(错误折叠),而致使蛋白质三维结构所应表达的功能出现错乱,使其丧失其生物学功能而带来的疾病。

迄今已发现 20 多种蛋白质的错误折叠与疾病相关,例如:神经退行性疾病如阿尔茨海默病(Alzheimer’ s disease , AD) ,  帕金森病(Parkinson’s disease , PD) ,亨廷顿舞蹈病(Huntington’sdisease ,HD) ,朊蛋白病(prion disease) , 家族性肌萎缩侧索硬化症(familial amyotrophic lateral sclerosis ,ALS)  等。 因此,对构象发生错误的蛋白质三维结构进行研究将有利于相关疾病的预防、诊断和治疗。


Proteopathy (Proteo- [pref. protein]; -pathy [suff. disease]; proteopathies pl.; proteopathic adj.) is the abnormal accumulation and toxicity of proteins in certain disease states.[1] The proteopathies (sometimes referred to as "proteinopathies") comprise more than 30 diseases that affect a variety of organs and tissues, including Alzheimer’s disease, Parkinson’s disease, type 2 diabetes, amyloidosis, selective hyperproteolytic diseases (e.g. critical illness myopathies or tumor cachexia), and a wide range of other disorders (see Table).[2][3][4][5][6][7]

The proteopathies also are called protein conformational diseases,[6] because a change in the 3-dimensional folding (conformation) of a protein increases the tendency of the protein to misfold and polymerize into aggregates that are resistant to clearance, and can become pathogenic. Because of the common structure of the polypeptide backbone, all proteins have the potential to misfold under some conditions.[8]

Only certain proteins are linked to proteopathy, possibly due to instability or other structural features of the monomeric protein that increase the probability of misconformation,[6][8] which in nearly all instances involves an increase in beta-sheet secondary structure.[8][6][9] Potential risk factors for proteopathic diseases augment the tendency of vulnerable proteins to self-assemble. They include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance.[6][8][1] Advancing age frequently is a risk factor.[1]

In some proteopathies, abnormal assembly can be templated on an exogenous protein, typically a misfolded form of the same protein.[10][11] In this way, the disease state can be induced in a susceptible host by the introduction of diseased tissue extract from an afflicted donor. The best known form of such infectious (or transmissible) proteopathy is prion disease, which can be transmitted by exposure of a host organism to purified prion protein in a disease-causing conformation.[12][13] There is now evidence that other proteopathies are inducible by a similar mechanism, including AA amyloidosis, apolipoprotein AII amyloidosis, and amyloidosis.[11][14] In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent.





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