The mid-nineteen century invention of subcellular fractionation and the application of electron microscopy to cell biology allowed us to discover the functional connections between the endoplasmic reticulum (ER) and Golgi apparatus in protein synthesis and secretion. This progress – which formed part of those steps forward resulting in the Nobel Prize for Physiology or Medicine in 1974 to Albert Claude, Christian de Duve and George Palade – opened the way to the discovery of intracellular membrane trafficking, the diverse compartments of the endomembrane system, and the secretory and endocytic pathways. The biosynthetic branch of the secretory pathway starts from the ER and leads to the Golgi apparatus as the first intermediate station. At the end of last century, the discovery of vesicle budding and fusion together with associated protein machinery, the continued refinement of electron microscopy, and the development of confocal microscopy and fluorescent protein tags – combining recombinant DNA and live imaging – have opened an intense and still-ongoing debate about the mechanistic aspects of the functional connections between compartments (Spang, 2013; Robinson et al., 2015). This is particularly important at ER exit, where thousands of proteins destined for secretion or different endomembrane compartments start their life.
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