Scientists discover how cells spot and destroy defective proteins in membranes
Researchers have identified the mechanism bacteria use to detect misfolded membrane proteins and eliminate them before they cause damage. The finding reveals that exposed water-loving amino acids act as a distress signal, enabling a quality-control protease called FtsH to target faulty proteins. Understanding this cellular surveillance system could inform drug design and protein engineering strategies across biotechnology and pharmaceuticals.
Originaltitel: Membrane-embedded polar residues target membrane proteins for degradation by the quality control protease FtsH
The biogenesis of membrane proteins (MPs) is inherently error-prone, and is therefore monitored by quality control mechanisms that remove faulty MPs. A key challenge for this surveillance is to recognize misfolded MPs, but how this is achieved remains poorly understood. Here we reveal how FtsH, the main MP quality control protease in Escherichia coli, specifically targets faulty MPs. By analyzing the in vivo degradation of two substrates, we show that lipid-facing polar residues trigger FtsH-mediated degradation. In folded MPs, such polar residues are usually buried in the protein core. Their exposure to the membrane can therefore signal misfolding and promote degradation. Strikingly, lipid-facing polar residues can even trigger degradation of a folded protein, and do not require the extended cytosolic regions typically needed for other FtsH substrates. Recognition depends on the FtsH transmembrane domain and on specific polar residues within it. Thus, sensing misfolding within the membrane helps maintain the integrity of the membrane proteome.