Determinants for regulation of precursor protein fate

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Chaperones and specific holdases participate in cytosolic transport events and very likely also in the intraorganellar distribution of proteins to the final target membranes. Recent observations challenge the assumed holdase function of chaperones of the Hsp70 and Hsp90 family in the delivery of proteins as an influence of these chaperones on preprotein stability was discovered. A similar discussion has been started for the holdase GET3, which is assumed to be involved in delivery of tail anchored proteins to the according membranes but also in the regulation of protein homeostasis. The molecular basis of these regulatory functions and the regulation between the two currently discussed functions in protein import/insertion and protein homeostasis are only rudimentarily understood. The recent findings pose three major challenges, which are thought to be addressed in the frame of the project: (i) we still need to identify putative cytosolic targeting factors; (ii) we have to decipher the regulation of preprotein transfer by chaperones and (iii) we will explore the GET3 holdase function and its integration in the cellular protein homeostasis network.