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Membranes and sorting
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Membranes and sorting Editorial overview Ira Mellman Address Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, PO Box 208002, New Haven, CT 06520-8002, USA Current Opinion in Cell Biology 1996, 8:497-498 © Current Biology Ltd ISSN 0955-0674
Understanding in cell biology, and probably in all of science, is a cyclical phenomenon. Entire fields, or portions of fields, appear to cycle continuously between periods of exquisite insight and periods of abject confusion. Remarkably, confusion appears to occur just after the articulation of a major conceptual advance that served to greatly clarify a problem of exceptional importance. Confusion, however, is itself a relative state of mind. We tend to forget that, with each turn of the cycle, our perceived lack of understanding is based on an ever broadening and strengthened information base where general concepts and the nature of individual proteins, genes, and functions remain sound and well established. Confusion typically reflects little more than a temporary inability to incorporate isolated pieces of new information into an existing paradigm. Most often it is simply the specifics of the paradigm that must be changed, and not the broader base upon which it was built. The area of cell biology concerned with the structure and function of cellular membranes has consistently proved to be one of the most rob'ust and rapidly moving. It is also one of the most visible areas of cell biology, perhaps because of the ease with which new information can be translated into fundamental principles. Although its 'knowledge cycle' may turn at particularly rapid rates, it has generated a remarkable amount of basic insight into issues that, until recently, were understood only at the level of static electron-microscopic images or superficial biochemistry. The past year has been no exception to this pattern, and this issue of Current Opinion in Cell Biology contains a series of articles that assess progress on different problems that presently encompass all stages of the cycle. It is up to the reader to decide which problem is at which stage, as this decision, too, is inherently relative and highly subjective. Perhaps the most mature problem in all of modern molecular membrane biology is that of protein translocation across intracellular membranes, particularly the endoplasmic reticulum (ER) membrane. It is almost 20 years since the groundwork was laid by the pioneering work of Gtinter Blobel and Bernhard Dobberstein. Their success in reconstituting the vectorial transport of newly
synthesized secretory proteins into isolated dog pancreas microsomes arguably represented the first in vitro assay for a complex transmembrane-transport phenomenon. Although this problem has been through many turns of the knowledge cycle, the strategy has been skillfully applied, and combined with both genetics and classical biochemistry, to bring us to a point at which many of the major membrane protein components involved in the translocation process have been identified and their activities elucidated in increasing detail. The first article, contributed by Rapoport, Rolls and Jungnickel (pp 499-504), comes from one of the world's leading groups in this area and summarizes our current state of understanding of protein translocation into the ER, together with a listing of the various ER components now known to play a role in the translocation process. Most remarkably, the 'paradox' of cotranslational insertion into ER membranes in mammalian cells versus post-translational insertion in yeast is close to being resolved, with both processes representing slight modifications of a single common mechanism rather than being representative of two distinct and evolutionarily diverse solutions to a common problem. Another protein-translocation system that has reached a similar state of understanding is the import of cytosolic precursor proteins into mitochondria. Here, if anything, the translocation process is even more complex in that as many as three translocation events across two membranes (the mitochondrial outer and inner membranes) are required for the proper compartmentalization of precursors. In addition, the translocation process has been tightly linked with the sequential unfolding and refolding of imported proteins before and following their translocation, respectively; both of these events are mediated by specific chaperones whose existence and functions have been revealed by the systematic reconstitution of mitochondrial import. The extraordinary progress in unraveling these events has been summarized by Lill, Nargang and Neupert (pp 505-512), whose efforts have been at the forefront of this important and exciting field. The third translocation problem addressed in this volume is that of protein targeting into peroxisomes. The study of the events involved in peroxisome biogenesis has yielded some remarkable surprises, such as the indication that translocation is not coupled to protein unfolding - - a situation which raises the issue of just how a folded and possibly globular protein can traverse a biological membrane. In this section, one of the world's leaders of the peroxisome field, Suresh Subramani (pp 513-518), reports on the dissection and analysis of the two parallel pathways
Membranes and sorting Editorial overview Ira Mellman Address Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, PO Box 208002, New Haven, CT 06520-8002, USA Current Opinion in Cell Biology 1996, 8:497-498 © Current Biology Ltd ISSN 0955-0674
Understanding in cell biology, and probably in all of science, is a cyclical phenomenon. Entire fields, or portions of fields, appear to cycle continuously between periods of exquisite insight and periods of abject confusion. Remarkably, confusion appears to occur just after the articulation of a major conceptual advance that served to greatly clarify a problem of exceptional importance. Confusion, however, is itself a relative state of mind. We tend to forget that, with each turn of the cycle, our perceived lack of understanding is based on an ever broadening and strengthened information base where general concepts and the nature of individual proteins, genes, and functions remain sound and well established. Confusion typically reflects little more than a temporary inability to incorporate isolated pieces of new information into an existing paradigm. Most often it is simply the specifics of the paradigm that must be changed, and not the broader base upon which it was built. The area of cell biology concerned with the structure and function of cellular membranes has consistently proved to be one of the most rob'ust and rapidly moving. It is also one of the most visible areas of cell biology, perhaps because of the ease with which new information can be translated into fundamental principles. Although its 'knowledge cycle' may turn at particularly rapid rates, it has generated a remarkable amount of basic insight into issues that, until recently, were understood only at the level of static electron-microscopic images or superficial biochemistry. The past year has been no exception to this pattern, and this issue of Current Opinion in Cell Biology contains a series of articles that assess progress on different problems that presently encompass all stages of the cycle. It is up to the reader to decide which problem is at which stage, as this decision, too, is inherently relative and highly subjective. Perhaps the most mature problem in all of modern molecular membrane biology is that of protein translocation across intracellular membranes, particularly the endoplasmic reticulum (ER) membrane. It is almost 20 years since the groundwork was laid by the pioneering work of Gtinter Blobel and Bernhard Dobberstein. Their success in reconstituting the vectorial transport of newly
synthesized secretory proteins into isolated dog pancreas microsomes arguably represented the first in vitro assay for a complex transmembrane-transport phenomenon. Although this problem has been through many turns of the knowledge cycle, the strategy has been skillfully applied, and combined with both genetics and classical biochemistry, to bring us to a point at which many of the major membrane protein components involved in the translocation process have been identified and their activities elucidated in increasing detail. The first article, contributed by Rapoport, Rolls and Jungnickel (pp 499-504), comes from one of the world's leading groups in this area and summarizes our current state of understanding of protein translocation into the ER, together with a listing of the various ER components now known to play a role in the translocation process. Most remarkably, the 'paradox' of cotranslational insertion into ER membranes in mammalian cells versus post-translational insertion in yeast is close to being resolved, with both processes representing slight modifications of a single common mechanism rather than being representative of two distinct and evolutionarily diverse solutions to a common problem. Another protein-translocation system that has reached a similar state of understanding is the import of cytosolic precursor proteins into mitochondria. Here, if anything, the translocation process is even more complex in that as many as three translocation events across two membranes (the mitochondrial outer and inner membranes) are required for the proper compartmentalization of precursors. In addition, the translocation process has been tightly linked with the sequential unfolding and refolding of imported proteins before and following their translocation, respectively; both of these events are mediated by specific chaperones whose existence and functions have been revealed by the systematic reconstitution of mitochondrial import. The extraordinary progress in unraveling these events has been summarized by Lill, Nargang and Neupert (pp 505-512), whose efforts have been at the forefront of this important and exciting field. The third translocation problem addressed in this volume is that of protein targeting into peroxisomes. The study of the events involved in peroxisome biogenesis has yielded some remarkable surprises, such as the indication that translocation is not coupled to protein unfolding - - a situation which raises the issue of just how a folded and possibly globular protein can traverse a biological membrane. In this section, one of the world's leaders of the peroxisome field, Suresh Subramani (pp 513-518), reports on the dissection and analysis of the two parallel pathways