How do Moonlighting Proteins get Targeted to More Than One Location in the Cell?

For example, cytosolic “housekeeping” enzymes in central metabolism that moonlight on the cell surface as a receptor not only need a binding site with which to interact with another protein, but they also they need a mechanism to be transported across the cell membrane and a mechanism to become attached to the cell surface. None of the intracellular/cell-surface moonlighting proteins have been found to possess a signal peptide for targeting to the cell membrane or other sequence motifs associated with other mechanisms of secretion. It is also important to note that only a small portion of each protein is partitioned to the cell surface while most of the protein remains in the cell cytoplasm. Once outside the cell, the intracellular/cell-surface proteins need a mechanism for attachment to the cell surface. There are several known sequence motifs for this purpose, for example the LPXTG motif that is involved in attaching proteins to the cell surface in Gram-positive bacteria (Schneewind et al. 1993); however, the intracellular/cell- surface moonlighting proteins do not possess any of these known cell-surface attachment motifs. How these intracellular proteins end up located outside of the cell and attached to the cell surface is an active area of inquiry in this field. In the case of bacterial pathogens, some of these processes might involve previously unknown mechanisms of secretion or attachment that could be targeted in the development of novel therapeutics.

What Changes in Expression Patterns Have Occurred to Enable the Protein to be Available in a New Time and Place to Perform a New Function?

In addition to changes in the protein sequence or structure itself, or association with new binding partners, changes in the expression pattern of the protein are often needed for a protein to perform a new function, for example, expression in multiple cell types and/or expression at additional times during development. These may be the result of changes in the promoter region or other regulatory sequences of the gene.

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