October 2011

A most hazardous journey

The production, sorting and selection of newly synthesized proteins in eukaryotes  

Meetings_Protein_SynthesisProteins possess a mind-boggling array of activities, but before they perform their diverse functions, they must be synthesized and fold with high fidelity. During or after synthesis, about one-third of all newly synthesized eukaryotic proteins enter the secretory pathway and therefore also must be transported into the endoplasmic reticulum, where they fold and are post-translationally modified. Secreted proteins that are improperly synthesized, transported or processed are recognized by components of a quality-control machinery that targets them for degradation. Because so many things can go wrong during the early life of a protein, it comes as no surprise that a significant number of human diseases are linked to protein biogenesis.

The four sessions in the “Protein Synthesis, Targeting and Quality-Control” theme will provide an overview and detail cutting-edge methods and discoveries related to these topics.

The ribosome and early folding decisions 

Proteins start their lives at the ribosome. From here, they must begin the complicated process of folding and being transported to their final destinations. This session will highlight our current mechanistic understanding of early steps in protein biogenesis.

Jody Puglisi (Stanford University School of Medicine) has pioneered the use of single-particle studies to understand the dynamics of protein synthesis, directly visualizing independent components during the translation cycle.

Wolfgang Wintermeyer (Max Planck Institute for Biophysical Chemistry in Göttingen) also will speak to the dynamics of the translation process, focusing on the nascent chain and its interactions.

Walid Houry (University of Toronto) will illuminate the roles of some of the ribosome’s partners, specifically discussing the role of chaperone assemblies.

Protein targeting and translocation 

Protein delivery is a highly regulated event, and we continually add additional levels of complexity to our understanding of this process. During this session, we will further our current understanding about the routes that proteins take on their journeys across membranes.

Peter Walter (University of California, San Francisco) has pioneered our understanding of protein targeting and will discuss novel insights into the events that deliver proteins to the endoplasmic reticulum membrane.

Gunnar von Heijne (University of Stockholm) will provide a detailed description of the requirements for transmembrane domain insertion mediated by the translocon.

William Clemons (California Institute of Technology) will describe new insights into novel pathways for the targeting of the special class of tail-anchored membrane proteins.

Are you a good protein or a bad protein? 

The next session, “Factors Modulating Protein Quality Control,” will highlight recent advances in our understanding of how proteins in the endoplasmic reticulum and in the cytoplasm misfold and are then recognized by distinct quality-control processes.

Jeffrey Brodsky (University of Pittsburgh) will describe novel approaches in which factors required for endoplasmic-reticulum-associated degradation, or ERAD, have been identified and characterized.

Richard Wojcikiewicz (State University of New York Upstate Medical School) will provide a fascinating example in which the regulated ERAD of a housekeeping protein in the endoplasmic reticulum, the IP3 receptor, is achieved.

Tricia Serio (Brown University) will discuss how things can go wrong on the other side of the membrane: Prions are infectious proteins that aggregate in the cytoplasm and cause disease. Her talk will feature new data on how prion conformation and chaperone association are linked to aggregate formation.

Protein quality control and disease

The last session will highlight some of the connections between defects in protein biogenesis and associated diseases.

First, Edward Fisher (New York University) will describe how apolipoprotein B is degraded in cells, an event that is connected intimately to lipid metabolism, cholesterol transport and heart disease.

Phyllis Hanson (Washington University School of Medicine) will discuss the molecular basis for a neurological disorder that arises from a defective form of an ER-resident, chaperone-like protein.

Finally, Jason Gestwicki (University of Michigan) will discuss new approaches to identifying small-molecule modulators of chaperone action and their use in disease models.

Meetings_Protein_Synthesis_Brodosky_JeffreyMeetings_Protein_Synthesis_Clemons_WilliamJeffrey L. Brodsky (jbrodsky@pitt.edu) is the Avinoff professor of biological sciences at the University of Pittsburgh, and William M. Clemons Jr.(clemons@caltech.edu) is an assistant professor of biochemistry at the California Institute of Technology.

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