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- Worms in space |
The degradation of proteins in the cell is critical for intracellular signaling and cell division. However, aberrant protein degradation results in muscle wasting and may give rise to several human diseases, such as cystic fibrosis and emphysema. The Jacobson and Brodsky laboratories are using model systems (C. elegans and yeast, respectively) to uncover the mechanisms by which specific proteins are selected and delivered to proteolytic "machines" in the cell. The use of these model systems permits a coordinated biochemical and genetic attack to follow the biogenesis and proteolysis of specific macromolecules, such as myosin, the cystic fibrosis transmembrane conductance regulator (CFTR), and peptide hormones. The role of intracellular signaling pathways in the degradation of these substrates is also being investigated. The Brodsky laboratory has collaborated in the development of a model by which mutated secretory proteins are targeted for degradation. In this model (see below), proteins in the endoplasmic reticulum (ER) are recognized as being mis-folded or mutated while they are associated with the translocation complex ("TC"). BiP is required to pull the molecule into the ER as it is tethered to the ribosome ("R"). Once a proteins is targeted for degradation, it is ubiquitinated ("UBQ") and with the help of heat shock proteins ("Hsp/Ssa"), is delivered to the proteasome ("P"), a cytosolic degradative machine that plays a vital role in the function of the immune system. (For further details please see Brodsky and McCracken 1997, and Brodsky et al. 1999).
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