Functional effects of protein variants

Abstract

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.

Keywords: Abundance; Activity; Affinity; Bioinformatics; Mutation; Protein function; Protein functional effect; Protein variation; Specificity.