University of Massachusetts Amherst
How Peptides Led the Way to Folding in the Cell
The protein folding problem was originally framed as the challenge of understanding how the amino acid sequence of a protein encodes its complex native structure. Early protein folding research focused on determining the pathway by which an unstructured polypeptide forms structure characteristic of the native state. This view of protein folding relied heavily on relationships between amino acid sequences and their preferred structural motifs such as helices, sheets and turns, many of which were established using model peptides. For example, my studies of cyclic peptides, begun in the Blout laboratory, were centered on improving our understanding of sequence preferences for reverse turns. A paradigm shift in protein folding research took place with the recognition that the folding reaction must be described in terms of ensembles of states and conformational search over a funnel-shaped energy landscape.
Ironically, at this point little attention was paid to the physiological context of protein folding. My laboratory’s eyes were opened to the in-vivo protein folding problem by our studies of signal sequences and their role in targeting proteins to the secretory pathway or to membrane locations. This work brought us into the cell biology of protein biosynthesis, localization, and quality control just at the time that the molecular chaperone concept was born. Our work with peptides enabled us to be swept up in the exciting science that ensued: the intersection of the fundamental principles of protein folding and the extremely challenging environment of the cell.
From this point on, we have sought to understand how molecular chaperones recognize clients that are unfolded (fully or partially) and the mechanisms whereby chaperones play roles in many processes in the cell, including but not restricted to the folding reaction. Most recently, we have focused on a central molecular chaperone family, the Hsp70s, which facilitate folding, inhibit aggregation, maintain proteins in unfolded states, and partner with other chaperones, all through a deceptively simple mechanism. This lecture will briefly chronicle my path from research on model peptides to studies of folding in the cell and describe our current emphasis: the substrate binding and allosteric mechanism of Hsp70s.