Protein intrinsic disorder and structure-function continuum

Abstract

The functional proteome of a given organism noticeably exceeds its corresponding genome due to various events at the DNA (genetic variations), mRNA (alternative splicing, alternative promoter usage, alternative initiation of translation, and mRNA editing), and protein levels (post-translational modifications) that results in the appearance of various proteoforms; i.e., different molecular forms in which the protein product of a single gene can be found. In addition to these induced proteoforms, basic (or intrinsic, or conformational) proteoforms are generated due to the presence of intrinsically disordered or structurally flexible regions in a protein. Furthermore, protein functionality can affect the structural ensemble of both conformational and induced proteoforms, and hence serves as a factor generating functioning proteoforms. Therefore, a single gene encodes for a wide array of different proteoforms, which represents the foundation for protein multifunctionality. In other words, instead of the classical protein structure-function paradigm rooted in the "one-gene-one-protein-one-function" model, a correlation between between protein structure and function is described by a more general "protein structure-function continuum" model, where a given protein exists as a dynamic conformational ensemble containing multiple proteoforms (conformational/basic, inducible/modified, and functioning) characterized by a broad spectrum of structural features and possessing various functional potentials.