Andrew Dillin, Pioneer Developmental Chair and an associate professor in the Molecular and Cell Biology Laboratory, uses the tiny roundworm Ceanorhabditis elegans to study the process of aging by looking at a hormone that is most widely recognized for its role in diabetes among humans: insulin. The insulin signaling pathway in worms is not only almost identical to that found in humans, but Dillin discovered that insulin also controls many physiological aspects in the worm's body, including reproduction and aging. In humans, interfering with insulin/IGF-1 signaling to generate a life-prolonging benefit would lead to type 2 diabetes and possibly cancer. In worms, larval development and reproduction are affected along with longevity.
Some of Dillin's earlier research had hinted at the possibility to genetically manipulate one element of the pathway without disrupting its additional functions, this led him to search for "specificity" factors that may control how and if insulin and IGF-1 impact a wide range of target genes. Recently, he and his team pinpointed a protein specifically responsible for extending lifespan and youthfulness without disrupting the worms' response to some forms of stress, development and fertility controlled by the insulin signaling pathway.
Additionally, Dillin is interested in age-onset neurodegenerative diseases. Like most neurodegenerative diseases, Alzheimer's disease usually appears late in life, raising the question of whether it is a direct and disastrous consequence of aging or if the toxic protein aggregates that cause the disease simply take a long time to form. He discovered that the harmful beta amyloid aggregates accumulate when aging impedes two molecular clean-up crews from getting rid of these toxic species.
Education
B.S., Biochemistry, University of Nevada, Reno
Ph.D., Molecular & Cell Biology, University of California, Berkeley
Awards and Honors
McKnight Neurosciences of Brain Disorders Award (2007)
Ellison Medical Foundation Award (2004-2008)
Larry L. Hillblom Junior Faculty Award (2003-2006)
American Diabetes Association Junior Faculty Award (2004-2006)
Damon Runyon-Walter Winchell Postdoctoral Fellowship, UC San Francisco (1999-2002)
Selected Publications
Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A. Opposing Activities Protect Against Age Onset Proteotoxicity. Science. 2006.
Wolff S, Ma H, Burch D, Maciel GA, Hunter T, Dillin A. SMK-1, an essential regulator of DAF-16-mediated longevity. Cell. 124(5):1039-53; 2006.
Raices M, Maruyama H, Dillin A, Karlseder J. Uncoupling of longevity and telomere length in C. elegans. PLoS Genet. (3):30; 2005.
Dillin, A., Hsu, A., Arantes-Oliveira, N., Lehrer-Graiwer, J., Hsin, H., Fraser, A. G., Kamath, R. V., Ahringer, J., Kenyon, C. Lifelong Rates of Behavior and Aging Specified by Respiratory Chain Activity During Development. Science. 298(5602):2398-401; 2002.
Dillin, A., Crawford, D. K., Kenyon C. Timing requirements for insulin signaling in C. elegans. Science. 298:830-4; 2002.
Arantes-Oliveira N, Apfeld J, Dillin A, Kenyon C. Regulation of life-span by germ-line stem cells in C. elegans. Science. 295(5554):502-5; 2002.
Friday, January 16, 2009
Michael G Rosenfeld
http://rosenfeldlab.ucsd.edu/
We are investigating the molecular strategies used to generate genome-wide, integrated transcriptional responses to the vast signaling network that regulates development and homeostasis. We are using genetic, biochemical and biological approaches to define the strategies used by the human body to specify modifications to development and differentiation of cells when genes are expressed. Our work has revealed unexpected gene-specific strategies that link regulated gene responses to other cellular response programs, including DNA damage and DNA repair. Defining these strategies has suggested new approaches to diseases, including growth defects, diabetes, arteriosclerosis, and several prevalent forms of cancer.
Regulatory Strategies in Development and Function of the Neuroendocrine System
Molecular Mechanisms of Regulated Gene Transcription
Neural Stem Cells--Corepressor Strategies in Neuronal Development
Macrophage: Cancer Cell Interactions in Breast and Prostate Cancers
Sensors and Signals--coactivator and corepressor complexes in genome-wide patterns of gene expression
Neurodegenerative Diseases
We are investigating the molecular strategies used to generate genome-wide, integrated transcriptional responses to the vast signaling network that regulates development and homeostasis. We are using genetic, biochemical and biological approaches to define the strategies used by the human body to specify modifications to development and differentiation of cells when genes are expressed. Our work has revealed unexpected gene-specific strategies that link regulated gene responses to other cellular response programs, including DNA damage and DNA repair. Defining these strategies has suggested new approaches to diseases, including growth defects, diabetes, arteriosclerosis, and several prevalent forms of cancer.
Regulatory Strategies in Development and Function of the Neuroendocrine System
Molecular Mechanisms of Regulated Gene Transcription
Neural Stem Cells--Corepressor Strategies in Neuronal Development
Macrophage: Cancer Cell Interactions in Breast and Prostate Cancers
Sensors and Signals--coactivator and corepressor complexes in genome-wide patterns of gene expression
Neurodegenerative Diseases
Tom A Rapoport
Department of Cell Biology
Harvard Medical School/HHMI
LHRRB Building, Room 613
240 Longwood Avenue, Boston, MA 02115-6091
tel: (617) 432-0637; fax: (617) 432-1190
email: tom_rapoport@hms.harvard.edu
Research Interests:
We are interested in the molecular mechanisms by which proteins are transported across the eukaryotic endoplasmic reticulum (ER) membrane or across the bacterial plasma membrane. Proteins are transported through a protein-conducting channel, formed from a conserved trimeric membrane protein complex, called the Sec61p complex in eukaryotes, and the SecY complex in prokaryotes. The channel is a passive pore that needs to associate with partners that provide the driving force for translocation. We know of three different pathways in which the channel functions.
The first is co-translational translocation, in which the ribosome is the major partner. Our present work concentrates on the structure of ribosome-channel complexes using electron cryo-microscopy single particle analysis (collaboration with the group of Christopher Akey at Boston University) and X-ray analysis.
The second mode is post-translational translocation in eukaryotes, in which another membrane protein complex, the Sec62/63p complex, and the luminal BiP protein are the partners.
The third mode is posttranslational translocation in bacteria, in which the ATPase SecA is the major partner. Our goal is to elucidate the mechanism by which the ATPase SecA provides the driving force for translocation.
A major effort in the lab is directed towards high-resolution structures of the translocation channel. We have obtained X-ray structures of the SecY complex from an archaebacterium, and more recently, of a SecA-channel complex. Together with biochemical data, these results suggest mechanisms for how the signal sequence of a substrate is recognized, how polypeptide chains are moved through the channel, and how trans-membrane segments of membrane proteins are integrated into the lipid bilayer.
We are also interested in the process by which misfolded ER proteins are transported back into the cytosol for degradation by the proteasome, a process called ERAD (for ER-associated protein degradation) or retro-translocation. We have provided evidence that there exist three ERAD pathways in yeast, depending on where the misfolded domain of the ER protein is located (ERAD-L for proteins with misfolded luminal domains, ERAD-M for proteins with misfolded intra-membrane domains, and ERAD-C for membrane proteins with misfolded cytosolic domains). The pathways use different ubiquitin-ligase complexes but converge at the Cdc48p ATPase complex (p97 or VCP complex in mammals). We are currently using translocation intermediates and crosslinking methods to identify the retro-translocation channel that likely exists at least for ERAD-L substrates.
A major effort in the lab concerns the mechanism by which the structure of the ER is generated and maintained. Our results show that the reticulons and DP1/Yop1p shape the tubular ER. We are interested in understanding how these proteins are regulated and how ER sheets are generated.
Other Projects Include:
1. The mechanism by which DNA is transported across membranes during the sporulation of B. subtilis.
2. The structure a bacterial homolog of the VKOR protein (vitamin K epoxide oxidoreductase).
3. The mechanism by which mRNA is transported in mammalian cells.
Selected Publications:
van den Berg, L., Clemons, W., Collinson, I., Hartmann, E., Modis, Y., Harrison, S.C., and Rapoport, T.A. (2004). X-ray structure of a protein-conducting channel. Nature 427: 36-44.
Carvalho, P., Goder, V., and Rapoport T.A. (2006). Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126: 361-373.
Voeltz, G.K., Prinz, W.A., Shibata, Y., Rist, J.M., and Rapoport, T.A. (2006). A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124: 573-86.
Rapoport, T.A. (2007). Protein translocation across the eukaryotic ER and bacterial plasma membranes. Nature 450: 663-669.
Zimmer, J., Nam, Y., and Rapoport, T.A. (2008). Structure of a complex of the ATPase SecA protein-translocation channel. Nature 455(7215): 936-43.
Harvard Medical School/HHMI
LHRRB Building, Room 613
240 Longwood Avenue, Boston, MA 02115-6091
tel: (617) 432-0637; fax: (617) 432-1190
email: tom_rapoport@hms.harvard.edu
Research Interests:
We are interested in the molecular mechanisms by which proteins are transported across the eukaryotic endoplasmic reticulum (ER) membrane or across the bacterial plasma membrane. Proteins are transported through a protein-conducting channel, formed from a conserved trimeric membrane protein complex, called the Sec61p complex in eukaryotes, and the SecY complex in prokaryotes. The channel is a passive pore that needs to associate with partners that provide the driving force for translocation. We know of three different pathways in which the channel functions.
The first is co-translational translocation, in which the ribosome is the major partner. Our present work concentrates on the structure of ribosome-channel complexes using electron cryo-microscopy single particle analysis (collaboration with the group of Christopher Akey at Boston University) and X-ray analysis.
The second mode is post-translational translocation in eukaryotes, in which another membrane protein complex, the Sec62/63p complex, and the luminal BiP protein are the partners.
The third mode is posttranslational translocation in bacteria, in which the ATPase SecA is the major partner. Our goal is to elucidate the mechanism by which the ATPase SecA provides the driving force for translocation.
A major effort in the lab is directed towards high-resolution structures of the translocation channel. We have obtained X-ray structures of the SecY complex from an archaebacterium, and more recently, of a SecA-channel complex. Together with biochemical data, these results suggest mechanisms for how the signal sequence of a substrate is recognized, how polypeptide chains are moved through the channel, and how trans-membrane segments of membrane proteins are integrated into the lipid bilayer.
We are also interested in the process by which misfolded ER proteins are transported back into the cytosol for degradation by the proteasome, a process called ERAD (for ER-associated protein degradation) or retro-translocation. We have provided evidence that there exist three ERAD pathways in yeast, depending on where the misfolded domain of the ER protein is located (ERAD-L for proteins with misfolded luminal domains, ERAD-M for proteins with misfolded intra-membrane domains, and ERAD-C for membrane proteins with misfolded cytosolic domains). The pathways use different ubiquitin-ligase complexes but converge at the Cdc48p ATPase complex (p97 or VCP complex in mammals). We are currently using translocation intermediates and crosslinking methods to identify the retro-translocation channel that likely exists at least for ERAD-L substrates.
A major effort in the lab concerns the mechanism by which the structure of the ER is generated and maintained. Our results show that the reticulons and DP1/Yop1p shape the tubular ER. We are interested in understanding how these proteins are regulated and how ER sheets are generated.
Other Projects Include:
1. The mechanism by which DNA is transported across membranes during the sporulation of B. subtilis.
2. The structure a bacterial homolog of the VKOR protein (vitamin K epoxide oxidoreductase).
3. The mechanism by which mRNA is transported in mammalian cells.
Selected Publications:
van den Berg, L., Clemons, W., Collinson, I., Hartmann, E., Modis, Y., Harrison, S.C., and Rapoport, T.A. (2004). X-ray structure of a protein-conducting channel. Nature 427: 36-44.
Carvalho, P., Goder, V., and Rapoport T.A. (2006). Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126: 361-373.
Voeltz, G.K., Prinz, W.A., Shibata, Y., Rist, J.M., and Rapoport, T.A. (2006). A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124: 573-86.
Rapoport, T.A. (2007). Protein translocation across the eukaryotic ER and bacterial plasma membranes. Nature 450: 663-669.
Zimmer, J., Nam, Y., and Rapoport, T.A. (2008). Structure of a complex of the ATPase SecA protein-translocation channel. Nature 455(7215): 936-43.
Susan Ferro-Novick
Professor of Cell Biology
Investigator, Howard Hughes Medical Institute
Phone: (203) 737-5207
Lab: (203) 737-4453/-4451
Fax: (203) 737-5246
e-mail: susan.ferronovick@yale.edu Department of Cell Biology
Yale Universtiy School of Medicine
333 Cedar Street
PO Box 208002
New Haven, CT 06520-8002
Vesicle traffic and organelle inheritance
The goal of our research program is to understand how the specificity of vesicle traffic is maintained and how organelles are inherited from mother to daughter cells.
Vesicle Traffic
For our studies on vesicle traffic, we have focused on the multiprotein complex called TRAPP. There are two forms of the TRAPP complex, TRAPP I and TRAPP II. TRAPP I is required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi, while TRAPP II is required for traffic from the early endosome to the Golgi and within the Golgi. Interestingly, spondyloepiphyseal dysplasia tardia, a recessive disorder in bone formation is caused by mutations in the human orthologue of a TRAPP subunit.
Using a vesicle binding assay that employs in vitro formed ER-derived vesicles and pure TRAPP I, we have demonstrated that TRAPP I specifically binds to ER to Golgi vesicles. These findings imply that TRAPP I plays a key role in conferring the specificity of ER to Golgi vesicle traffic. TRAPP I binds to coated ER-derived vesicle via an interaction with the coat cargo adapter complex (see Figure), linking TRAPP I dependent vesicle binding to cargo recognition. Once binding occurs, TRAPP I activates the small GTPase Ypt1p, converting it from its GDP-bound to its GTP-bound form. The activation of Ypt1p by TRAPP I may be the signal that the vesicle has reached its correct acceptor compartment. This then leads to the recruitment of other components, such as Uso1p. The pairing of the SNAREs, a class of membrane proteins that are required for membrane fusion, is the final step in docking an ER-derived vesicle to the Golgi.
Organelle Inheritance
It is the goal of these studies to define the process by which the ER is delivered into daughter cells. To achieve this goal a genetic approach has been used to identify the machinery that moves ER tubules from mother to daughter cells. This approach has led to the identification of a collection of genes whose products are required for ER inheritance. A track and motor that moves ER tubules into daughter cells, as well as a putative receptor for cortical ER in daughter cells have been identified. Orthologues of these components are present in higher cells.
Selected Publications
Cai, H., Reinisch, K. and Ferro-Novick, S. 2007. Coats, Tethers , Rabs and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev Cell 12: 671-682.
Cai, H., Yu, S., Menon, S., Cai, Y., Lazarova, D., Fu, C., Reinisch, K., Hay, J. C. and Ferro-Novick, S. 2007. TRAPPI tethers COPII vesicles by binding the coat subunit Sec23p. Nature 445: 941-944.
(Commentaries on this paper appeared in Dev Cell and Curr Biol)
Du, Y., Walker, L., Novick, P. and Ferro-Novick, S. 2006. Ptc1p regulates cortical ER inheritance via Slt2p. EMBO J. 25: 4413-4422.
(This paper was highlighted in EMBO J)
Yu, S., Satoh, A., Pypaert, M., Muller, K., Hay, J.C. and Ferro-Novick, S. 2006. mBet3p is required for homotypic COPII vesicle tethering in mammalian cells. J. Cell Biol. 174:359-368.
DeCreane, J.O., Coleman, J., Estrada de Martin, P., Pypaert,M., Anderson, S., Yates III, J.R., Ferro-Novick, S and Novick, P. 2006. Rtn1p is involved in structuring the cortical ER. Mol. Biol. Cell 17:3009-3020.
Cai, H., Zhang, Y., Pypaert, M., Walker, L. and Ferro-Novick, S. 2005. Trs120p mediates traffic from the early endosome to a late Golgi compartment. J. Cell Biol. 171:823-833.
Estrada de Martin,P., Novick,P. and Ferro-Novick,S. 2005. The organization, structure and inheritance of the ER in higher and lower eukaryotes. Biochem. Cell Biol. 83:752-761.
Investigator, Howard Hughes Medical Institute
Phone: (203) 737-5207
Lab: (203) 737-4453/-4451
Fax: (203) 737-5246
e-mail: susan.ferronovick@yale.edu Department of Cell Biology
Yale Universtiy School of Medicine
333 Cedar Street
PO Box 208002
New Haven, CT 06520-8002
Vesicle traffic and organelle inheritance
The goal of our research program is to understand how the specificity of vesicle traffic is maintained and how organelles are inherited from mother to daughter cells.
Vesicle Traffic
For our studies on vesicle traffic, we have focused on the multiprotein complex called TRAPP. There are two forms of the TRAPP complex, TRAPP I and TRAPP II. TRAPP I is required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi, while TRAPP II is required for traffic from the early endosome to the Golgi and within the Golgi. Interestingly, spondyloepiphyseal dysplasia tardia, a recessive disorder in bone formation is caused by mutations in the human orthologue of a TRAPP subunit.
Using a vesicle binding assay that employs in vitro formed ER-derived vesicles and pure TRAPP I, we have demonstrated that TRAPP I specifically binds to ER to Golgi vesicles. These findings imply that TRAPP I plays a key role in conferring the specificity of ER to Golgi vesicle traffic. TRAPP I binds to coated ER-derived vesicle via an interaction with the coat cargo adapter complex (see Figure), linking TRAPP I dependent vesicle binding to cargo recognition. Once binding occurs, TRAPP I activates the small GTPase Ypt1p, converting it from its GDP-bound to its GTP-bound form. The activation of Ypt1p by TRAPP I may be the signal that the vesicle has reached its correct acceptor compartment. This then leads to the recruitment of other components, such as Uso1p. The pairing of the SNAREs, a class of membrane proteins that are required for membrane fusion, is the final step in docking an ER-derived vesicle to the Golgi.
Organelle Inheritance
It is the goal of these studies to define the process by which the ER is delivered into daughter cells. To achieve this goal a genetic approach has been used to identify the machinery that moves ER tubules from mother to daughter cells. This approach has led to the identification of a collection of genes whose products are required for ER inheritance. A track and motor that moves ER tubules into daughter cells, as well as a putative receptor for cortical ER in daughter cells have been identified. Orthologues of these components are present in higher cells.
Selected Publications
Cai, H., Reinisch, K. and Ferro-Novick, S. 2007. Coats, Tethers , Rabs and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev Cell 12: 671-682.
Cai, H., Yu, S., Menon, S., Cai, Y., Lazarova, D., Fu, C., Reinisch, K., Hay, J. C. and Ferro-Novick, S. 2007. TRAPPI tethers COPII vesicles by binding the coat subunit Sec23p. Nature 445: 941-944.
(Commentaries on this paper appeared in Dev Cell and Curr Biol)
Du, Y., Walker, L., Novick, P. and Ferro-Novick, S. 2006. Ptc1p regulates cortical ER inheritance via Slt2p. EMBO J. 25: 4413-4422.
(This paper was highlighted in EMBO J)
Yu, S., Satoh, A., Pypaert, M., Muller, K., Hay, J.C. and Ferro-Novick, S. 2006. mBet3p is required for homotypic COPII vesicle tethering in mammalian cells. J. Cell Biol. 174:359-368.
DeCreane, J.O., Coleman, J., Estrada de Martin, P., Pypaert,M., Anderson, S., Yates III, J.R., Ferro-Novick, S and Novick, P. 2006. Rtn1p is involved in structuring the cortical ER. Mol. Biol. Cell 17:3009-3020.
Cai, H., Zhang, Y., Pypaert, M., Walker, L. and Ferro-Novick, S. 2005. Trs120p mediates traffic from the early endosome to a late Golgi compartment. J. Cell Biol. 171:823-833.
Estrada de Martin,P., Novick,P. and Ferro-Novick,S. 2005. The organization, structure and inheritance of the ER in higher and lower eukaryotes. Biochem. Cell Biol. 83:752-761.
Gunter blobel
http://www.rockefeller.edu/labheads/blobel/blobel-lab.html
John D. Rockefeller, Jr. Professor; Investigator, HHMI
The unidirectional translocation of thousands of distinct proteins across specific intracellular membranes is mediated by "signal" sequences. On average, a signal sequence consists of a stretch of ~15 amino acid residues that is either a transient or permanent part of the protein to be translocated. The signal sequence functions essentially as a ligand. Each signal sequence is membrane specific and is decoded by a complex machinery that is restricted in its location to one particular cellular membrane.
Two distinct mechanisms of translocation have so far been discovered. In one mechanism translocation proceeds through protein conducting channels. The diameter of the aqueous center of these protein conducting channels is limited (~2 nm) so that passage of a protein can proceed only in its unfolded configuration. A number of polypeptide binding proteins assist in keeping the protein to be translocated in an unfolded configuration. Protein conducting channels have recently been detected electrosphysiologically in the endoplasmic reticulum and the prokaryotic plasma membrane. These channels were found to be gated open by the signal sequence. The channel closes after translocation of the chain is completed. In addition to opening and closing across the membrane, the channel must also be able to open and close in a second dimension, namely to the lipid bilayer. This is necessary to permit integration of proteins into membranes. A protein to be integrated into the membrane uses a signal sequence to open the channel. Translocation proceeds until a "stop transfer" sequence of the translocating polypeptide chain interacts with the channel to open it laterally to the lipid bilayer. As a result, the segment of the chain that is located in the channel would be displaced into the bilayer with the channel simultaneously closing in both dimensions. Similar protein conducting channels are likely to exist in the outer as well as the inner membrane of chloroplasts and mitochondria, in the thylakoid membrane of chloroplasts, and in the peroxisomal membrane. The great challenge ahead is to isolate and to characterize these protein conducting channels.
The mechanism of protein translocation across the nuclear pore complex (NPC) is distinct from that of translocation across the above-described protein conducting channels. NPCs are huge organelles (estimated molecular mass: 125 million daltons) that are suspended in 100-nm wide circular openings in the nuclear envelope. An NPC can open to 25 nm in diameter. For passage across, proteins do not need to be kept in an unfolded configuration. Unlike protein conducting channels, NPCs are unable to integrate proteins into the lipid bilayer. Furthermore, transport across the NPC is bidirectional. Also, transport is not limited to proteins but includes ribonucleoproteins (RNPs). An in vitro system for signal sequence-mediated protein uptake into the nucleus has been used to isolate and to characterize cytosolic factors that are required for import. Similar in vitro RNP export systems are being developed to study export of RNPs. NPCs have been purified in quantity from yeast. An estimated 100 or so proteins make up the NPC. The challenge ahead here is to understand the structure and function of these NPC proteins and of NPC as a whole.
John D. Rockefeller, Jr. Professor; Investigator, HHMI
The unidirectional translocation of thousands of distinct proteins across specific intracellular membranes is mediated by "signal" sequences. On average, a signal sequence consists of a stretch of ~15 amino acid residues that is either a transient or permanent part of the protein to be translocated. The signal sequence functions essentially as a ligand. Each signal sequence is membrane specific and is decoded by a complex machinery that is restricted in its location to one particular cellular membrane.
Two distinct mechanisms of translocation have so far been discovered. In one mechanism translocation proceeds through protein conducting channels. The diameter of the aqueous center of these protein conducting channels is limited (~2 nm) so that passage of a protein can proceed only in its unfolded configuration. A number of polypeptide binding proteins assist in keeping the protein to be translocated in an unfolded configuration. Protein conducting channels have recently been detected electrosphysiologically in the endoplasmic reticulum and the prokaryotic plasma membrane. These channels were found to be gated open by the signal sequence. The channel closes after translocation of the chain is completed. In addition to opening and closing across the membrane, the channel must also be able to open and close in a second dimension, namely to the lipid bilayer. This is necessary to permit integration of proteins into membranes. A protein to be integrated into the membrane uses a signal sequence to open the channel. Translocation proceeds until a "stop transfer" sequence of the translocating polypeptide chain interacts with the channel to open it laterally to the lipid bilayer. As a result, the segment of the chain that is located in the channel would be displaced into the bilayer with the channel simultaneously closing in both dimensions. Similar protein conducting channels are likely to exist in the outer as well as the inner membrane of chloroplasts and mitochondria, in the thylakoid membrane of chloroplasts, and in the peroxisomal membrane. The great challenge ahead is to isolate and to characterize these protein conducting channels.
The mechanism of protein translocation across the nuclear pore complex (NPC) is distinct from that of translocation across the above-described protein conducting channels. NPCs are huge organelles (estimated molecular mass: 125 million daltons) that are suspended in 100-nm wide circular openings in the nuclear envelope. An NPC can open to 25 nm in diameter. For passage across, proteins do not need to be kept in an unfolded configuration. Unlike protein conducting channels, NPCs are unable to integrate proteins into the lipid bilayer. Furthermore, transport across the NPC is bidirectional. Also, transport is not limited to proteins but includes ribonucleoproteins (RNPs). An in vitro system for signal sequence-mediated protein uptake into the nucleus has been used to isolate and to characterize cytosolic factors that are required for import. Similar in vitro RNP export systems are being developed to study export of RNPs. NPCs have been purified in quantity from yeast. An estimated 100 or so proteins make up the NPC. The challenge ahead here is to understand the structure and function of these NPC proteins and of NPC as a whole.
Pietro De Camilli
Pietro De Camilli is an Italian-American biologist and Eugene Higgins Professor of Cell Biology at Yale University School of Medicine. He is also an Investigator at Howard Hughes Medical Institute.
De Camilli completed his M.D. degree from the University of Milan in Italy. He then went to the United States and did his postdoctoral studies at Yale University.
De Camilli is known for contributions that has been to demonstrate the crucial role of protein-lipid interactions and phosphoinositide metabolism in the control of membrane traffic at the synapse.
He has received several awards and honors for his work. He was elected to the European Molecular Biology Organization in 1987. In 2001, he was elected to the National Academy of Sciences and to the American Academy of Arts and Sciences. In 1990 he received the Max-Planck-Forschungspreis together with Reinhard Jahn (Max Planck Institute of Psychiatry).
During synaptic transmission, neurotransmitter-containing vesicles fuse with the plasma membrane, releasing neurotransmitters into the synaptic space by exocytosis. In the subsequent seconds, vesicle membranes are reinternalized and reused for the next generation of synaptic vesicles. Over the last 25 years, Pietro De Camilli has studied the molecular mechanisms involved in this intricate cycle of membrane traffic and has identified and characterized numerous proteins that participate in the process. Trained as an M.D., he has also made significant contributions toward understanding human diseases of the nervous system that involve autoimmunity against synaptic proteins. Because the synaptic vesicle is a powerful model organelle for studying fundamental mechanisms in membrane-cytoskeletal interactions, membrane fusion, and membrane budding, De Camilli's discoveries are relevant to secretory and endocytic mechanisms in many fields beyond neurotransmission.
De Camilli completed his M.D. degree from the University of Milan in Italy. He then went to the United States and did his postdoctoral studies at Yale University.
De Camilli is known for contributions that has been to demonstrate the crucial role of protein-lipid interactions and phosphoinositide metabolism in the control of membrane traffic at the synapse.
He has received several awards and honors for his work. He was elected to the European Molecular Biology Organization in 1987. In 2001, he was elected to the National Academy of Sciences and to the American Academy of Arts and Sciences. In 1990 he received the Max-Planck-Forschungspreis together with Reinhard Jahn (Max Planck Institute of Psychiatry).
During synaptic transmission, neurotransmitter-containing vesicles fuse with the plasma membrane, releasing neurotransmitters into the synaptic space by exocytosis. In the subsequent seconds, vesicle membranes are reinternalized and reused for the next generation of synaptic vesicles. Over the last 25 years, Pietro De Camilli has studied the molecular mechanisms involved in this intricate cycle of membrane traffic and has identified and characterized numerous proteins that participate in the process. Trained as an M.D., he has also made significant contributions toward understanding human diseases of the nervous system that involve autoimmunity against synaptic proteins. Because the synaptic vesicle is a powerful model organelle for studying fundamental mechanisms in membrane-cytoskeletal interactions, membrane fusion, and membrane budding, De Camilli's discoveries are relevant to secretory and endocytic mechanisms in many fields beyond neurotransmission.
Prominent researchers- HHMI
Michael D Ehlers.
http://www.ehlerslab.org/
Michael D. Ehlers, M.D., Ph.D. (Young Investigator 2000) of Duke University Medical Center, aims to determine the molecular mechanisms which regulate the localization and function of NMDA receptors. These receptors play important roles in learning and memory, brain development, and neuropsychiatric disease. Dr. Ehlers will identify new regulatory molecules associated with NMDA receptors, determine the effect of phosphorylation (addition of a phosphate molecule) on these receptors, and determine which domains of the NMDA receptor localize it to synapses (the spaces between adjacent neurons). These studies may provide a crucial step in understanding the function of the NMDA receptors, which may facilitate the design of rational strategies for the treatment of neurologic and psychiatric disease, such as schizophrenia.
http://www.ehlerslab.org/
Michael D. Ehlers, M.D., Ph.D. (Young Investigator 2000) of Duke University Medical Center, aims to determine the molecular mechanisms which regulate the localization and function of NMDA receptors. These receptors play important roles in learning and memory, brain development, and neuropsychiatric disease. Dr. Ehlers will identify new regulatory molecules associated with NMDA receptors, determine the effect of phosphorylation (addition of a phosphate molecule) on these receptors, and determine which domains of the NMDA receptor localize it to synapses (the spaces between adjacent neurons). These studies may provide a crucial step in understanding the function of the NMDA receptors, which may facilitate the design of rational strategies for the treatment of neurologic and psychiatric disease, such as schizophrenia.
Friday, January 9, 2009
Subscribe to:
Posts (Atom)