The phrase “finding a needle in a haystack” refers to the difficulty of locating a specific target among a large number of very similar objects. Living cells face a comparable challenge whenever they carry out seek and destroy missions aimed at broken or otherwise undesirable molecules. Scientists are still figuring out how these quality control systems can quickly and accurately pick out the few unwanted molecules that occasionally appear in crowds of normal molecules. Understanding how quality control systems find their targets could help to combat disease like cancer, neurodegenerative diseases and cystic fibrosis, all of which have been linked to quality control systems targeting too few or too many proteins.
Msp1 is a quality control protein that resides on the outer surfaces of two compartments within cells: mitochondria and peroxisomes. Previous work showed that when a protein called Pex15, which is normally found in peroxisomes, is mistakenly sent to mitochondria it is rapidly eliminated by Msp1. Weir et al. set out to understand how Msp1 at peroxisomes avoids turning over Pex15.
To investigate how Msp1 distinguishes peroxisome-localized from mitochondria-localized Pex15, Weir et al. monitored Pex15 turnover at individual organelles in live yeast cells using fluorescence microscopy. Although Msp1 did not normally recognize Pex15 at peroxisomes, Weir et al. found that Msp1 blocked over-loading of peroxisomes with Pex15. Comparing how quickly cells eliminated excess Pex15 at peroxisomes with predictions from mathematical models showed that Pex15 normally “matures” from an Msp1-sensitive to an Msp1-insensitive state. Further experiments revealed that Pex15 binds to another protein found in peroxisomes, called Pex3, which protects Pex15 from Msp1; however, over-loading peroxisomes with excess Pex15 produced an unbound (and Msp1-sensitive) Pex15 population. By contrast, occasional Pex15 molecules that reached mitochondria (which lack Pex3) remained immature and sensitive to Msp1.
Proteins like Msp1 are also found in humans, and Weir et al. hope that a better understanding of how Msp1 works in yeast will help scientists studying human disorders caused by defects in similar quality control systems.