Rebellion of the deregulated regulators: What is the clinical relevance of studying intrinsically disordered proteins?

Abstract

Since at the molecular level, almost all physiological processes are defined by the specific activities of specific proteins or protein groups, dysfunction and deregulation of these proteins are linked to the pathogenesis of various maladies. Therefore, to get to the roots of the pathological processes and find appropriate cure for the related diseases, one should clearly know the connections between protein-centric physiology and pathology. This logic represents premises of the medical protein science, where one is looking for the connections between the ‘right’ protein structure and normal function to understand how dysfunction can be linked back to the ‘wrong’ structure and assuming that fixing such ‘wrong’ structure can serve as a means to restore a normal function and therefore cure a disease. Even though mutations in a gene encoding a culprit protein represent the major reason for this protein to gain ‘wrong’ structure, dysfunctionality can also be caused by the distortion of any means from a very broad arsenal of cellular proteostasis-related mechanisms evolved to control and regulate protein folding, structure, and function. Although for the first time, proteins were described by the Dutch chemist Gerardus Johannes Mulder (1802–1880) as enormous molecules, with empirical formula for fibrin and egg albumin being C400H620N100O120P1S1, in his 1838 paper ‘On the composition of some animal substances’ first published in French [1] and translated to German in 1839 [2], they gained serious attention of researchers only after their polypeptide nature discovered independently in 1902 by a German chemist Hermann Emil Louis Fischer (1852–1919) [3] and an early protein scientist Franz Hofmeister (1850–1922) [4] was connected to the enzymatic activity by an American chemist, James B. Sumner (1887–1955), who, in 1926, showed that the enzyme urease is a protein that can be isolated and crystallized [5]. Curiously, as early as in 1894, enzymatic activity was proposed by Emil Fischer to follow his classical ‘lock-and-key’ model [6]. This concept was eventually elaborated into the famous protein structure-function paradigm, where the amino acid sequence determines a uniquely folded 3D structure that can be visualized in the crystalline state and that, in turn, defines the unique protein function [7]. As a result, in most of the almost 185 years of their history (and definitely since 1894), proteins were equated to enzymes, being considered as biological catalysts, while many other functions of these biological macromolecules and their intriguing potential to be multifunctional were mostly ignored.