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The Trigger Factor Chaperone Encapsulates and Stabilizes Partial Folds of Substrate Proteins.

Singhal K, Vreede J, Mashaghi A, Tans SJ, Bolhuis PG - PLoS Comput. Biol. (2015)

Bottom Line: Unfolded chains are kinetically trapped when bound to TF, which suppresses the formation of transient, non-native end-to-end contacts.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.

View Article: PubMed Central - PubMed

Affiliation: van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.

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.

No MeSH data available.


Crystal structures of.A. Trigger factor (TF, PDB code: 1W26). The surface of the protein is shown as transparent wire-mesh around the backbone. The surfaces of TF domains are colored differently: N-terminal in blue, Linker in indigo, PPIase domain in red, HA1-linker in yellow, Arm1 in orange, and Arm2 in green; B. Maltose binding protein (MBP, PDB code: 1JW4). The surface of MBP is colored gray, while the structure is colored black. Truncate of MBP’s folding intermediates: C. P2 with a backbone in orange and D. P1 with a backbone in red.
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pcbi.1004444.g001: Crystal structures of.A. Trigger factor (TF, PDB code: 1W26). The surface of the protein is shown as transparent wire-mesh around the backbone. The surfaces of TF domains are colored differently: N-terminal in blue, Linker in indigo, PPIase domain in red, HA1-linker in yellow, Arm1 in orange, and Arm2 in green; B. Maltose binding protein (MBP, PDB code: 1JW4). The surface of MBP is colored gray, while the structure is colored black. Truncate of MBP’s folding intermediates: C. P2 with a backbone in orange and D. P1 with a backbone in red.

Mentions: 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 a general ATP-independent chaperone [4, 5] found in bacteria (e.g., E. coli) [6] and chloroplasts [7, 8]. Bound to the ribosome exit tunnel [9], TF interacts with the emerging nascent chains, and shields them from interactions with other cellular components [10]. TF can also remain associated with polypeptide chains when they are released into the cytosol, and interact with fully folded proteins before their assembly into larger protein complexes [11]. At the ribosome exit tunnel, TF adopts an extended conformation necessary for unfolded substrate interaction [10]. Its dragon-like structure (see Fig 1A) is composed of three domains: N-terminal (residues 1–149); Polypropyl Isomerase or PPIase domain (residues 150–245), also referred to as “Head”; and C-terminal (residues 246–432), which forms the cradle of TF. 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). A “Linker” (residues 112–149) connects the core of N-terminal (residues 1–111) to the Head. In separate studies, 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 a structural collapse of TF in isolation. It has been suggested that its flexibility and promiscuous surface allow TF to interact with substrates of diverse compositions and sizes [8, 11, 14].


The Trigger Factor Chaperone Encapsulates and Stabilizes Partial Folds of Substrate Proteins.

Singhal K, Vreede J, Mashaghi A, Tans SJ, Bolhuis PG - PLoS Comput. Biol. (2015)

Crystal structures of.A. Trigger factor (TF, PDB code: 1W26). The surface of the protein is shown as transparent wire-mesh around the backbone. The surfaces of TF domains are colored differently: N-terminal in blue, Linker in indigo, PPIase domain in red, HA1-linker in yellow, Arm1 in orange, and Arm2 in green; B. Maltose binding protein (MBP, PDB code: 1JW4). The surface of MBP is colored gray, while the structure is colored black. Truncate of MBP’s folding intermediates: C. P2 with a backbone in orange and D. P1 with a backbone in red.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4626277&req=5

pcbi.1004444.g001: Crystal structures of.A. Trigger factor (TF, PDB code: 1W26). The surface of the protein is shown as transparent wire-mesh around the backbone. The surfaces of TF domains are colored differently: N-terminal in blue, Linker in indigo, PPIase domain in red, HA1-linker in yellow, Arm1 in orange, and Arm2 in green; B. Maltose binding protein (MBP, PDB code: 1JW4). The surface of MBP is colored gray, while the structure is colored black. Truncate of MBP’s folding intermediates: C. P2 with a backbone in orange and D. P1 with a backbone in red.
Mentions: 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 a general ATP-independent chaperone [4, 5] found in bacteria (e.g., E. coli) [6] and chloroplasts [7, 8]. Bound to the ribosome exit tunnel [9], TF interacts with the emerging nascent chains, and shields them from interactions with other cellular components [10]. TF can also remain associated with polypeptide chains when they are released into the cytosol, and interact with fully folded proteins before their assembly into larger protein complexes [11]. At the ribosome exit tunnel, TF adopts an extended conformation necessary for unfolded substrate interaction [10]. Its dragon-like structure (see Fig 1A) is composed of three domains: N-terminal (residues 1–149); Polypropyl Isomerase or PPIase domain (residues 150–245), also referred to as “Head”; and C-terminal (residues 246–432), which forms the cradle of TF. 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). A “Linker” (residues 112–149) connects the core of N-terminal (residues 1–111) to the Head. In separate studies, 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 a structural collapse of TF in isolation. It has been suggested that its flexibility and promiscuous surface allow TF to interact with substrates of diverse compositions and sizes [8, 11, 14].

Bottom Line: Unfolded chains are kinetically trapped when bound to TF, which suppresses the formation of transient, non-native end-to-end contacts.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.

View Article: PubMed Central - PubMed

Affiliation: van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.

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.

No MeSH data available.