The 2003 Lectures in Biology: Signal Peptides and Cell TraffickingNot too long ago we considered the cell as a "bag of enzymes". We know now that nothing could be further away from the truth, for any, but especially for the eucaryotic cell. As we know it today, the eucaryotic cell is a marvel of architectural organization and micro-compartmentalization. The various cellular compartments, or organelles as we call them, are mostly bound by lipid membranes. However, they are to variable degrees, coupled by both mass and energy exchanges. This coupling is not uniform in space nor in time. There exist highly dynamic, delicately balanced feed-back "traffic circuits" of mass and energy that govern the life states of a cell. These circuits utilize molecules, many of which (but not all), representprimary expressions of the genetic information of the cell.However, the patterns of these circuits are not immediately under DNA control. They represent emerging propertiesof the "appropriately" situated macromolecular assemblies, which although were synthesized under the DNA code,were subsequently organized and compartmentalized according to epigenetic, physicochemical rules and patterns. To simplify, the organization of a cell can be compared to that of a big city such as Athens, Paris, or Stockholm. In order to reach its correct destination, a letter meant for a resident of that city has to be provided with an address label and a zip code. How, then, the various pieces of "cellular mail"(various proteins for example) "find" their optimum destination places within the various compartments of the cell?What dictates their re-localization from one compartment to the other? What is the molecular basis of the apparent specificity of such macromolecular trafficking? What is the chemical nature of the "mailing address" and which is (are) the delivery carrier(s)? The Nobel Assembly at Karolinska Institutet in Stockholm, Swedenawarded the Nobel Prize in Physiology / Medicine for 1999 to Gόnter Blobel, for his discovery that "proteins have intrinsic signals that govern their transport and localization in the cell." How do newly synthesized proteins find their correct destinations within a cell, and how are they able to pass across the tightly sealed intracellular membranes? These were the central questions that Gόnter Blobel began to address in the late 1960s. In 1980 Dr. Blobel proposed that newly-made proteins are targeted to and imported into the various organelles within the cell by built-in signal sequences. The signals are short stretches of amino acids encoded by the gene specifying the protein. They can be located at either end of the protein, or somewhere internally. This proposal has been extensively confirmed and is now universally accepted. Present view of protein synthesis and translocation across the endoplasmic reticulum (ER) implicates a specificsignal peptide (a short sequence of amino acids within the newly-synthesized protein), which emerges from the ribosome and binds to the signal-recognition particle (SRP). The SRP-ribosome complex then docks to the SRP-receptor and channel ("translocon") on the ER. Next, the SRP dissociates from the receptor and the nascent polypeptide chain is translocated through the channel into the ER lumen. The signal peptide is finally cleaved and the protein is secreted out of the cell. Since the original proposal by Blobel, the signal peptide concept has been expanded by his work and that of several major laboratories and the field has mushroomed, and now occupies the mainstream of cellular biology. It has served to discover and describe, in some instances in atomic detail, special macromolecular machines dedicated to the control of the intracellular traffic. Some examples of such processes are: nucleo-cytoplasmic exchanges; transport into and out of mitochondria and chloroplasts; ER-Golgi-Endosome-Cell surface exchanges. etc.Depending on the mechanism of their operation, these processes can be categorized in gated, transmebrane and vesiculartransport process. The significance of these process in the overall welfare of the cell, indeed the organism, can be underscored by the many inherited diseases which develop when proteins are mislocalized in the cell due to errors in targeting signals and transport. One example is "primary hyperoxaluria," a rare disease, which results in kidney stones already at an early age. A signal in the enzyme alanine:glyoxylate aminotransferase normally directs it to the peroxisome. In patients, this signal is altered and the protein is mislocalized to the mitochondrion where it is unable to perform its normal function. The Lecture series this year will focus on the fundamental description of the above-mentioned phenomena and will attempt to develop unifying principles the govern them. The spectrum of the Lectures will be broad, providing the foundations as well as the latest concepts in this field of research. MOVIE: A very informative movie describing the processes addressed by the lectures can be viewed at http://www.rockefeller.edu/pubinfo/proteintarget.html WORKSHOP: Since the advances in this field depend heavily on the contributions of various imaging methodologies, a session has been planned to provide practical demonstrations and hands-on experience with some of the techniques frequently used by lead researches of this field.The students will be presented with the opportunity to prepare samples and obtain "primary images" by various microscopic techniques.Subsequently, some of the images will be subjected to algorithms of image averaging and enhancement with the purpose of uncovering symmetries and other hidden structural information of the primary image. Günter Blobel
Prof., Rockefeller University Nobel Prize (1999) in Medicine Ueli Aebi Prof., University of Basel Elena Conti Group Leader, European Molecular Biology Laboratory Spyros Georgatos Prof., University of Ioannina Iain Mattaj Scientific Director, European Molecular Biology Laboratory Kostas Tokatlidis Lister Fellow, University of Manchester Assist. Prof. University of Crete and FORTH
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