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Structures of eukaryotic ribosomal stalk proteins and its complex with trichosanthin, and their implications in recruiting ribosome-inactivating proteins to the ribosomes.

Choi AK, Wong EC, Lee KM, Wong KB - Toxins (Basel) (2015)

Bottom Line: Recent studies have pointed to the involvement of the C-terminal domain of the eukaryotic stalk proteins in facilitating the toxic action of RIPs.This review highlights how structural studies of eukaryotic stalk proteins provide insights into the recruitment of RIPs to the ribosomes.Since the C-terminal domain of eukaryotic stalk proteins is involved in specific recognition of elongation factors and some eukaryote-specific RIPs (e.g., trichosanthin and ricin), we postulate that these RIPs may have evolved to hijack the translation-factor-recruiting function of ribosomal stalk in reaching their target site of rRNA.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, the Chinese University of Hong Kong, Shatin, Hong Kong, China. s1155004528@cuhk.edu.hk.

ABSTRACT
Ribosome-inactivating proteins (RIP) are RNA N-glycosidases that inactivate ribosomes by specifically depurinating a conserved adenine residue at the α-sarcin/ricin loop of 28S rRNA. Recent studies have pointed to the involvement of the C-terminal domain of the eukaryotic stalk proteins in facilitating the toxic action of RIPs. This review highlights how structural studies of eukaryotic stalk proteins provide insights into the recruitment of RIPs to the ribosomes. Since the C-terminal domain of eukaryotic stalk proteins is involved in specific recognition of elongation factors and some eukaryote-specific RIPs (e.g., trichosanthin and ricin), we postulate that these RIPs may have evolved to hijack the translation-factor-recruiting function of ribosomal stalk in reaching their target site of rRNA.

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Structural insights into how eukaryotic stalk recruits trichosanthin (TCS) to the α-sarcin/ricin loop (SRL). The structural model of eukaryotic stalk complex created as described [27] was docked to the crystal structure of yeast ribosome [22]. P0 (cyan) binds two copies of P1/P2 heterodimers via their N-terminal domains (NTD) (magenta). The C-terminal domain (CTD) of P1/P2 (red) is connected to the NTD via a flexible linker (salmon). The consensus sequence (SDDDMGFGLFD) at the CTD forms a complex with trichosanthin (green), in which the K173, R174 and K177 form favorable charge-charge interactions with the DDD motif of P1/P2 (inset). The normal function of the hydra-like structure of eukaryotic stalk, which can extend up to 125 Å from the stalk base, is to recruit elongation factors to GTPase association center of ribosomes. It is postulated that TCS gains access to the SRL by hijacking this elongation-factor-recruiting machinery of eukaryotic ribosomes.
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toxins-07-00638-f002: Structural insights into how eukaryotic stalk recruits trichosanthin (TCS) to the α-sarcin/ricin loop (SRL). The structural model of eukaryotic stalk complex created as described [27] was docked to the crystal structure of yeast ribosome [22]. P0 (cyan) binds two copies of P1/P2 heterodimers via their N-terminal domains (NTD) (magenta). The C-terminal domain (CTD) of P1/P2 (red) is connected to the NTD via a flexible linker (salmon). The consensus sequence (SDDDMGFGLFD) at the CTD forms a complex with trichosanthin (green), in which the K173, R174 and K177 form favorable charge-charge interactions with the DDD motif of P1/P2 (inset). The normal function of the hydra-like structure of eukaryotic stalk, which can extend up to 125 Å from the stalk base, is to recruit elongation factors to GTPase association center of ribosomes. It is postulated that TCS gains access to the SRL by hijacking this elongation-factor-recruiting machinery of eukaryotic ribosomes.

Mentions: Despite recent advances in the structural studies of ribosomes [33,34], the CTD of ribosomal stalks are not defined due to their intrinsic flexibility. Molecular modelling was used to generate structural models of ribosomal stalks by fitting the structures of individual stalk protein complexes to the structures of bacterial [11], archaeal [17] and eukaryotic [27] ribosomes. For example, we have recently determined the solution structure of full-length human P1/P2 heterodimer by NMR spectroscopy [27]. While the N-terminal dimerization domain of P1/P2 is well structured, the C-terminal tails of P1/P2 are disordered and can extend up to 125 Å away from the dimerization domain. NMR relaxation measurement showed that the C-terminal tails are flexible with significantly faster effective correlation time for the reorientation of the backbone amide group [27]. A common structural insight derived from these structural models is that multiple copies of the CTD of stalk proteins (P1/P2 or L12) are connected via a flexible linker region to the NTD, which binds to the spine-helix of L10 or P0. Presumably, the hydra-like structures of ribosomal stalk and the long flexible linkers allow the CTD of stalk proteins to reach out and fetch elongation factors to the GTPase association center of ribosomes, where GTP hydrolysis is stimulated to drive protein synthesis (Figure 2) [11,17].


Structures of eukaryotic ribosomal stalk proteins and its complex with trichosanthin, and their implications in recruiting ribosome-inactivating proteins to the ribosomes.

Choi AK, Wong EC, Lee KM, Wong KB - Toxins (Basel) (2015)

Structural insights into how eukaryotic stalk recruits trichosanthin (TCS) to the α-sarcin/ricin loop (SRL). The structural model of eukaryotic stalk complex created as described [27] was docked to the crystal structure of yeast ribosome [22]. P0 (cyan) binds two copies of P1/P2 heterodimers via their N-terminal domains (NTD) (magenta). The C-terminal domain (CTD) of P1/P2 (red) is connected to the NTD via a flexible linker (salmon). The consensus sequence (SDDDMGFGLFD) at the CTD forms a complex with trichosanthin (green), in which the K173, R174 and K177 form favorable charge-charge interactions with the DDD motif of P1/P2 (inset). The normal function of the hydra-like structure of eukaryotic stalk, which can extend up to 125 Å from the stalk base, is to recruit elongation factors to GTPase association center of ribosomes. It is postulated that TCS gains access to the SRL by hijacking this elongation-factor-recruiting machinery of eukaryotic ribosomes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4379515&req=5

toxins-07-00638-f002: Structural insights into how eukaryotic stalk recruits trichosanthin (TCS) to the α-sarcin/ricin loop (SRL). The structural model of eukaryotic stalk complex created as described [27] was docked to the crystal structure of yeast ribosome [22]. P0 (cyan) binds two copies of P1/P2 heterodimers via their N-terminal domains (NTD) (magenta). The C-terminal domain (CTD) of P1/P2 (red) is connected to the NTD via a flexible linker (salmon). The consensus sequence (SDDDMGFGLFD) at the CTD forms a complex with trichosanthin (green), in which the K173, R174 and K177 form favorable charge-charge interactions with the DDD motif of P1/P2 (inset). The normal function of the hydra-like structure of eukaryotic stalk, which can extend up to 125 Å from the stalk base, is to recruit elongation factors to GTPase association center of ribosomes. It is postulated that TCS gains access to the SRL by hijacking this elongation-factor-recruiting machinery of eukaryotic ribosomes.
Mentions: Despite recent advances in the structural studies of ribosomes [33,34], the CTD of ribosomal stalks are not defined due to their intrinsic flexibility. Molecular modelling was used to generate structural models of ribosomal stalks by fitting the structures of individual stalk protein complexes to the structures of bacterial [11], archaeal [17] and eukaryotic [27] ribosomes. For example, we have recently determined the solution structure of full-length human P1/P2 heterodimer by NMR spectroscopy [27]. While the N-terminal dimerization domain of P1/P2 is well structured, the C-terminal tails of P1/P2 are disordered and can extend up to 125 Å away from the dimerization domain. NMR relaxation measurement showed that the C-terminal tails are flexible with significantly faster effective correlation time for the reorientation of the backbone amide group [27]. A common structural insight derived from these structural models is that multiple copies of the CTD of stalk proteins (P1/P2 or L12) are connected via a flexible linker region to the NTD, which binds to the spine-helix of L10 or P0. Presumably, the hydra-like structures of ribosomal stalk and the long flexible linkers allow the CTD of stalk proteins to reach out and fetch elongation factors to the GTPase association center of ribosomes, where GTP hydrolysis is stimulated to drive protein synthesis (Figure 2) [11,17].

Bottom Line: Recent studies have pointed to the involvement of the C-terminal domain of the eukaryotic stalk proteins in facilitating the toxic action of RIPs.This review highlights how structural studies of eukaryotic stalk proteins provide insights into the recruitment of RIPs to the ribosomes.Since the C-terminal domain of eukaryotic stalk proteins is involved in specific recognition of elongation factors and some eukaryote-specific RIPs (e.g., trichosanthin and ricin), we postulate that these RIPs may have evolved to hijack the translation-factor-recruiting function of ribosomal stalk in reaching their target site of rRNA.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, the Chinese University of Hong Kong, Shatin, Hong Kong, China. s1155004528@cuhk.edu.hk.

ABSTRACT
Ribosome-inactivating proteins (RIP) are RNA N-glycosidases that inactivate ribosomes by specifically depurinating a conserved adenine residue at the α-sarcin/ricin loop of 28S rRNA. Recent studies have pointed to the involvement of the C-terminal domain of the eukaryotic stalk proteins in facilitating the toxic action of RIPs. This review highlights how structural studies of eukaryotic stalk proteins provide insights into the recruitment of RIPs to the ribosomes. Since the C-terminal domain of eukaryotic stalk proteins is involved in specific recognition of elongation factors and some eukaryote-specific RIPs (e.g., trichosanthin and ricin), we postulate that these RIPs may have evolved to hijack the translation-factor-recruiting function of ribosomal stalk in reaching their target site of rRNA.

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