Multiple Forms of Multifunctional Proteins in Health and Disease

Abstract

Protein science has moved from a focus on individual molecules to an integrated perspective in which proteins emerge as dynamic players with multiple functions, rather than monofunctional specialists. Annotation of the full functional repertoire of proteins has impacted the fields of biochemistry and genetics, and will continue to influence basic and applied science questions-from the genotype-to-phenotype problem, to our understanding of human pathologies and drug design. In this review, we address the phenomena of pleiotropy, multidomain proteins, promiscuity, and protein moonlighting, providing examples of multitasking biomolecules that underlie specific mechanisms of human disease. In doing so, we place in context different types of multifunctional proteins, highlighting useful attributes for their systematic definition and classification in future research directions.

Phase separation by the SARS-CoV-2 nucleocapsid protein: Consensus and open questions

“…Finally, the sequential publication model conceivably could affect the number of distinct functions discovered for a particular protein if initial reports of protein function lead to less experimental exploration for additional functions, which is especially relevant for multi-functional J o u r n a l P r e -p r o o f proteins (89). The diversity of studies on N-protein PS has linked this behavior to a remarkable array of possible in vivo functions, which may have been facilitated by parallel exploration.…”

Plasma Membrane Effects of Sphingolipid-Synthesis Inhibition by Myriocin in CHO Cells: A Biophysical and Lipidomic Study

“…The main difference between the two approaches is that LY-B cells lack a functional SPT complex because they cannot synthesize the LCB1 subunit, while the myriocin-mediated inhibition only blocks the SPT function, but the protein is still present. This may have important implications, for example the drug-inhibited protein may lack a certain activity but may still interact with some binding partners, as many proteins have multiple activities and/or functions and may participate in multiple disparate pathways, processes, and/or multiprotein complexes and structures [48][49][50] .…”

RHAMM Is a Multifunctional Protein That Regulates Cancer Progression

“…The one gene-one enzyme hypothesis proposed by Beadle and Tatum in 1941 [ 1 ], stating that genes produce protein products with a single function, helped shape our understanding of biochemical processes. However, the concept of protein function has since evolved in complexity, with many studies demonstrating that cell signaling can be highly context-dependent, allowing for the ability of single proteins to exert multiple and often opposing functions depending on cell state (e.g., proliferating, senescent, stem-like), environmental signals and protein subcellular compartmentalization [ 2 , 3 ]. However, classifying multifunctional proteins has been challenging.…”

“…Often, proteins acquire new functions with evolution, which generates novelty and complexity by building upon pre-existing domain structures [ 19 ]. Therefore, we use the term multifunctional [ 2 , 18 ] rather than moonlighting in describing the multiple functions of RHAMM. Here, we posit that RHAMM initially functioned as a heparin-binding protein that was co-opted to also bind to HA when this glycosaminoglycan appeared relatively late in evolution.…”