Abstract
How chaperones interact with protein chains to assist in their folding is a central open question in biology. Obtaining atomistic insight is challenging in particular, given the transient nature of the chaperone-substrate complexes and the large system sizes. Recent single-molecule experiments have shown that the chaperone Trigger Factor (TF) not only binds unfolded protein chains, but can also guide protein chains to their native state by interacting with partially folded structures. Here, we used all-atom MD simulations to provide atomistic insights into how Trigger Factor achieves this chaperone function. Our results indicate a crucial role for the tips of the finger-like appendages of TF in the early interactions with both unfolded chains and partially folded structures. Unfolded chains are kinetically trapped when bound to TF, which suppresses the formation of transient, non-native end-to-end contacts. Mechanical flexibility allows TF to hold partially folded structures with two tips (in a pinching configuration), and to stabilize them by wrapping around its appendages. This encapsulation mechanism is distinct from that of chaperones such as GroEL, and allows folded structures of diverse size and composition to be protected from aggregation and misfolding interactions. The results suggest that an ATP cycle is not required to enable both encapsulation and liberation.
Highlights
While many proteins can successfully fold independently and spontaneously in vitro [1], folding within the cell is facilitated by molecular chaperones [2, 3]
Trigger Factor (TF) is an ATP-independent chaperone protein that assists in folding and prevents misfolding
We found that TF interacts with folded structures with the ends of its flexible appendages, especially N-terminal, forming a “Touching complex”
Summary
While many proteins can successfully fold independently and spontaneously in vitro [1], folding within the cell is facilitated by molecular chaperones [2, 3]. Bound to the ribosome exit tunnel [9], TF interacts with the emerging nascent chains, and shields them from interactions with other cellular components [10]. At the ribosome exit tunnel, TF adopts an extended conformation necessary for unfolded substrate interaction [10]. The C-terminal comprises of a long helical linker (residues 246–302), named “HA1-linker,” with two arm-like extensions—“Arm1” (residues 303–359) and “Arm2” (residues 360–415). Singhal, et al [12], and Thomas, et al [13], have used molecular dynamics simulations to reveal a surprising structural flexibility enabled by the hinge-like motions of linkers, which can drive doi:10.1371/journal.pcbi.1004444.g001
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