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Blobel's Contributions to the Field of Intracellular Protein Trafficking Following is a partial timelline of Günter Blobel's original, groundbreaking accomplishments: 1971 Proposed, with David Sabatini, that information for translocation of secretory proteins across the endoplasmic reticulum membrane resides in the NH2 terminal sequence. 1975 Developed the first cell-free system that faithfully reproduces protein translocation. This system became the paradigm for all other subsequently developed cell-free translocation systems (bacteria, mitochondria, chloroplasts, peroxisomes). More importantly, it provided the opportunity for extensive biochemical analysis of protein translocation. Expanded and shaped the proposal he and Sabatini made in 1971 into the "signal hypothesis." Determined the partial primary structure of signal sequences of several presecretory proteins by Edman degradation. 1977 First demonstrated that a nucleus-encoded, cytosol-synthesized protein of the chloroplast stroma is synthesized as a precursor, consistent with the idea that it contains a transient, chloroplast-targeted signal sequence. 1978 Provided the first example of an integral membrane protein shown to contain an NH2 termnal sequence extension that is the structural and functional equivalent of the signal sequence of presecretory proteins. Established for the first time a cell-free protein translocation system that mimicked the integration of a bacterial integral membrane protein into the bacterial plasma membrane. First demonstrated a membrane-associated bacterial signal peptidase. 1979 First demonstrated that nucleus-encoded, cystosol-synthesized mitochondrial matrix proteins are synthesized as larger precursors, and developed the first cell-free system that mimics protein import into mitochondria. First achieved the cell-free synthesis of a precursor for a lysosomal protein and translocation into microsomal vesicles. Elucidated, by Edman degradation, the primary structure of the first chloroplast stroma-targeted signal sequence. 1980 Extended the signal hypothesis to a general hypothesis on intracellular protein traffic and membrane biogenesis, and proposed the concept of "topogenic" sequences. First isolated component-catalyzing, signal sequence-mediated translocation across the ER. 1981 Showed that the isolated protein specifically recognizes signal sequences of nascent presecretory proteins, and named it the "signal recognition protein," or SRP. Postulated the existence of an "SRP receptor" in the microsomal membrane. Elucidated the primary structure of the first signal sequence for a lysosomal protein. 1982 Showed that SRP contains a 7S RNA molecule in the stoichiometry of one 7S RNA and one each of six different proteins. The term SRP now stands for "signal recognition particle." Purified the predicted SRP receptor from microsomal membranes. Elucidated the first primary structure for a signal sequence that targets proteins to mitochondria, this time by cDNA cloning rather than by Edman degradation. 1983 Demonstrated that the SRP receptor functions in targeting by releasing the signal sequence from SRP, and SRP from the ribosome. 1986 Purified the ER-associated signal peptidase as a complex of five polypeptide chains. 1988 Identified a "signal sequence receptor" for protein import into chloroplasts. 1989 First isolated a specific signal recognition factor that binds to signal sequences of bacterial presecretory protein. 1990 Completely solubilized ribosome-stripped and salt-extracted microsomal membranes by detergents. Removal of the detergents yielded reconstituted vesicles that are fully translocation-competent. This result was a crucial condition for the biochemical analyses of membrane proteins required for translocation, such as the SRP receptor, the protein conducting channel and other yet-to-be-identified membrane proteins. Identified a mitochondrial "signal sequence receptor" for protein import into yeast mitochondria. Cloned and sequenced the cDNA for the import receptor for chloroplast. 1991 Demonstrated the existence of a protein-conducting channel in the ER by electrophysiological procedures. 1992 Demonstrated that signal peptides are sufficient for opening the protein-conducting channels. 1993 Identified the requirement for the ATP binding protein RAN in nuclear transport. 1994 Identified the protein translocation machinery of chloroplasts. 1996 Showed that p10, a protein with a previously unknown function, plays a major role in the import of proteins into the nucleus. 1997 Observed the protein-conducting channels bound to ribosomes using cryo-electron microscopy Identified the pathway used to import ribosome proteins into the nucleus. 1999 Determined the crystal structures of the nuclear transport factors karyopherin alpha and beta. |
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