Journal
BIOMOLECULES
Volume 12, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/biom12020209
Keywords
multidomain proteins; IDPs; crowding; protein-protein interactions
Categories
Funding
- Italian Ministero dellIstruzione dellUniversita e della Ricerca (Progetto di Interesse Invecchiamento)
- Sapienza University of Rome [RP11715C34AEAC9B, RM1181641C2C24B9, RM11916B414C897E, RG12017297FA7223, AR22117A3CED340A]
- ACIP grant from Institut Pasteur Paris [ACIP 485-21]
- Associazione Italiana per la Ricerca sul Cancro [24551]
- Regione Lazio [A0375-2020-36559]
- European Unions Horizon 2020 research and Innovation programme under the Marie Sklodowska-Curie Grant [860517]
- Istituto Pasteur Italia
- FIRC-Associazione Italiana per la Ricerca sul Cancro (Filomena Todini fellowship)
- Marie Curie Actions (MSCA) [860517] Funding Source: Marie Curie Actions (MSCA)
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The majority of our knowledge about protein properties comes from in vitro studies on isolated globular domains, but many proteins in eukaryotic cells have more complex structures. The discovery of intrinsic disorder in up to 40% of eukaryotic proteins has revolutionized our understanding of protein structure and function. In addition, proteins often have multiple domains that interact with each other, and they function within a crowded intracellular environment. This review highlights the importance of considering these factors in studying protein folding and function.
The vast majority of our current knowledge about the biochemical and biophysical properties of proteins derives from in vitro studies conducted on isolated globular domains. However, a very large fraction of the proteins expressed in the eukaryotic cell are structurally more complex. In particular, the discovery that up to 40% of the eukaryotic proteins are intrinsically disordered, or possess intrinsically disordered regions, and are highly dynamic entities lacking a well-defined three-dimensional structure, revolutionized the structure-function paradigm and our understanding of proteins. Moreover, proteins are mostly characterized by the presence of multiple domains, influencing each other by intramolecular interactions. Furthermore, proteins exert their function in a crowded intracellular milieu, transiently interacting with a myriad of other macromolecules. In this review we summarize the literature tackling these themes from both the theoretical and experimental perspectives, highlighting the effects on protein folding and function that are played by (i) flanking disordered tails; (ii) contiguous protein domains; (iii) interactions with the cellular environment, defined as quinary structures. We show that, in many cases, both the folding and function of protein domains is remarkably perturbed by the presence of these interactions, pinpointing the importance to increase the level of complexity of the experimental work and to extend the efforts to characterize protein domains in more complex contexts.
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