Understanding protein multifunctionality: from short linear motifs to cellular functions

Abstract

Moonlighting proteins perform multiple unrelated functions without any change in polypeptide sequence. They can coordinate cellular activities, serving as switches between pathways and helping to respond to changes in the cellular environment. Therefore, regulation of the multiple protein activities, in space and time, is likely to be important for the homeostasis of biological systems. Some moonlighting proteins may perform their multiple functions simultaneously while others alternate between functions due to certain triggers. The switch of the moonlighting protein's functions can be regulated by several distinct factors, including the binding of other molecules such as proteins. We here review the approaches used to identify moonlighting proteins, existing repositories. We particularly emphasise the role played by short linear motifs and PTMs as regulatory switches of moonlighting functions.

The role of 3’UTR-protein complexes in the regulation of protein multifunctionality and subcellular localization

“…The assembly of 3'UTR-complexes may provide the molecular context and proximity necessary for protein moonlighting functions. Indeed, a large number of intermediate proteins are kinases that can modify nascent proteins, illustrating the fact that moonlighting functions may be partly commanded by short linear motifs 17,48 . Recently, it has been shown that 4 out of 9 S. cerevisiae protein complexes that form co-translationally 49 , possibly according to a 3'UTR-complex formation model 50 , involve 6 known multifunctional and moonlighting yeast proteins 49 .…”

Multiple Forms of Multifunctional Proteins in Health and Disease

“…Post-translational modifications involved in the modulation of moonlighting activities have been associated to the development of human disease. Phosphorylation, acetylation, and ubiquitination -among other protein modificationsaffect the cellular localization and the binding affinity of proteins to other molecules (Jeffery, 2016;Zanzoni et al, 2019). For example, the S-nitrosylation of the glyceraldehyde 3-phosphate dehydrogenase (G3PDH) protein promotes the shift from the catalytic function to a protein-binding function (Hara et al, 2005).…”

Ubiquitin Dynamics in Stem Cell Biology: Current Challenges and Perspectives

“…Many DUBs and E3 Ub ligases exhibit additional functional domains and short‐linear motifs that are currently overlooked. These short‐linear motifs, often occurring in disordered regions of a protein, mediate transient and reversible interactions . DUBs and E3 Ub ligases may have multiple potential regulatory functions linking ubiquitin dynamics with cell metabolism, translation, or mRNA biology.…”

“…These short-linear motifs, often occurring in disordered regions of a protein, mediate transient and reversible interactions. [103] DUBs and E3 Ub ligases may have multiple potential regulatory functions linking ubiquitin dynamics with cell metabolism, translation, or mRNA biology. It will be important to design proper separation-of-function mutations in order to clarify the role of such motifs and domains in future assays.…”