Department of Experimental Medical Science, BMC B13, Lund University, SE-22 184, Lund, Sweden.
Biochimie. 2021 Jan;180:104-120. doi: 10.1016/j.biochi.2020.10.009. Epub 2020 Oct 23.
Genetic and other variations frequently affect protein functions. Scientific articles can contain confusing descriptions about which function or property is affected, and in many cases the statements are pure speculation without any experimental evidence. To clarify functional effects of protein variations of genetic or non-genetic origin, a systematic conceptualisation and framework are introduced. This framework describes protein functional effects on abundance, activity, specificity and affinity, along with countermeasures, which allow cells, tissues and organisms to tolerate, avoid, repair, attenuate or resist (TARAR) the effects. Effects on abundance discussed include gene dosage, restricted expression, mis-localisation and degradation. Enzymopathies, effects on kinetics, allostery and regulation of protein activity are subtopics for the effects of variants on activity. Variation outcomes on specificity and affinity comprise promiscuity, specificity, affinity and moonlighting. TARAR mechanisms redress variations with active and passive processes including chaperones, redundancy, robustness, canalisation and metabolic and signalling rewiring. A framework for pragmatic protein function analysis and presentation is introduced. All of the mechanisms and effects are described along with representative examples, most often in relation to diseases. In addition, protein function is discussed from evolutionary point of view. Application of the presented framework facilitates unambiguous, detailed and specific description of functional effects and their systematic study.
遗传和其他变异经常影响蛋白质的功能。科学文章可能包含关于哪个功能或属性受到影响的混淆描述，在许多情况下，这些陈述纯粹是推测，没有任何实验证据。为了澄清遗传或非遗传来源的蛋白质变异的功能影响，引入了一种系统的概念化和框架。该框架描述了蛋白质在丰度、活性、特异性和亲和力方面的功能效应，以及允许细胞、组织和生物体耐受、避免、修复、减轻或抵抗（TARAR）这些效应的对策。讨论的丰度效应包括基因剂量、限制表达、定位错误和降解。酶病、对动力学的影响、变构和蛋白质活性的调节是变体对活性影响的子主题。特异性和亲和力的变异结果包括混杂性、特异性、亲和力和兼职性。TARAR 机制通过包括伴侣蛋白、冗余、鲁棒性、渠道化以及代谢和信号转导重布线在内的主动和被动过程来纠正变异。引入了一个实用的蛋白质功能分析和呈现框架。所有的机制和效应都有描述，并附有代表性的例子，大多数情况下与疾病有关。此外，还从进化的角度讨论了蛋白质功能。所提出的框架的应用促进了功能影响的明确、详细和具体的描述及其系统研究。
