Molecular chaperones are important protein quality control machinery that prevent the aggregation and/or promote the folding of proteins in the cell. Their dysfunction can lead to the accumulation of misfolded proteins, which has been linked to many neurodegenerative diseases. In eukaryotic cells, a complex chaperone network has evolved for the dedicated folding of newly synthesized proteins. This robust network includes different types of chaperones with distinct but partially overlapping functions. An analysis of the cytosolic Hsp70s SSA and SSB in S. cerevisiae demonstrated that structurally similar chaperones have different contributions to de novo folding and can act in a sequential manner in a "folding pathway" within the chaperone network. The activity of these chaperones is modulated by a host of cofactors. Here, we identified a novel cofactor of cytosolic Hsp70s, the Hsp110 SSE, that functions to modulate Hsp70 association to newly made proteins. Hsp110s likely represent general regulators of Hsp70s as they are conserved across eukaryotic organisms and cellular compartments.; A more downstream component of the chaperone network is the cytosolic chaperonin complex TRiC/CCT, which comprises the only chaperone complex for which each of its divergent subunits is essential to cellular life. The identification of the TRiC substrate repertoire and subsequent bioinformatics analysis revealed the chaperonin's preference for large, hydrophobic proteins with extensive beta-sheet structure. These proteins have complex topologies and are predicted to be slow-folding and aggregation-prone. Furthermore, most substrates belong to larger protein complexes, suggesting that the function of TRiC may have diversified to include the incorporation of substrate proteins into higher order assemblies. Finally, the preponderance of large, multidomain proteins in the TRiC Interactome suggest that TRiC, together with the eukaryotic chaperone network, is specialized for the folding of multidomain proteins. It is likely that this specialized folding machinery has enabled the emergence of larger multidomain proteins that are less abundant in prokaryotic and archaeal organisms.
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