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The similarity between N-terminal targeting signals for protein import into different organelles and its evolutionary relevance.

Kunze M, Berger J - Front Physiol (2015)

Bottom Line: The structural similarity of N-terminal targeting signals poses a challenge to the specificity of protein transport, but allows the generation of ambiguous targeting signals that mediate dual targeting of proteins into different compartments.Dual targeting might represent an advantage for adaptation processes that involve a redistribution of proteins, because it circumvents the hierarchy of targeting signals.Thus, the co-existence of two equally functional import pathways into peroxisomes might reflect a balance between evolutionary constant and flexible transport routes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna Vienna, Austria.

ABSTRACT
The proper distribution of proteins between the cytosol and various membrane-bound compartments is crucial for the functionality of eukaryotic cells. This requires the cooperation between protein transport machineries that translocate diverse proteins from the cytosol into these compartments and targeting signal(s) encoded within the primary sequence of these proteins that define their cellular destination. The mechanisms exerting protein translocation differ remarkably between the compartments, but the predominant targeting signals for mitochondria, chloroplasts and the ER share the N-terminal position, an α-helical structural element and the removal from the core protein by intraorganellar cleavage. Interestingly, similar properties have been described for the peroxisomal targeting signal type 2 mediating the import of a fraction of soluble peroxisomal proteins, whereas other peroxisomal matrix proteins encode the type 1 targeting signal residing at the extreme C-terminus. The structural similarity of N-terminal targeting signals poses a challenge to the specificity of protein transport, but allows the generation of ambiguous targeting signals that mediate dual targeting of proteins into different compartments. Dual targeting might represent an advantage for adaptation processes that involve a redistribution of proteins, because it circumvents the hierarchy of targeting signals. Thus, the co-existence of two equally functional import pathways into peroxisomes might reflect a balance between evolutionary constant and flexible transport routes.

No MeSH data available.


Protein transport routes from the cytosol into peroxisomes, mitochondria, chloroplasts, and the ER: The transport routes are depicted schematically to highlight certain players3. (A)Peroxisomes. Proteins encoding either a PTS1 or a PTS2 are folded within the cytosol and interact with the appropriated receptor proteins, Pex5 or the Pex7/co-receptor complex. This induces the translocation of cargo loaded receptors to the docking complex (DC), where they integrate into the peroxisomal membrane and release the cargo into the lumen. Finally, Pex5 and the Pex7/co-receptor complex are ubiquitylated by a specific ubiquitination machinery (UB) and recycled into the cytosol by an ATP driven extraction exerted by the receptor extraction machinery (REM). Soluble proteins reach the peroxisomal matrix in a folded state, but PTS2-carrying proteins are processed by the peroxisomal processing peptidase (PPP). (B)Mitochondria. Proteins encoding a presequence are translated within the cytosol, but remain in an unfolded state due to their association with proteins of the Hsp70 family. These complexes are transferred by the help of an additional cytosolic factor to a protein complex at the outer mitochondrial membrane (TOM), where the preprotein sequentially interacts with the receptors for soluble proteins (Tom20 and Tom22), before it is handed over to the pore forming translocon (Tom40). The preprotein crosses the outer mitochondrial membrane in an unfolded state and interacts with a protein complex in the inner mitochondrial membrane (TIM). The binding to Tim40 mediates the interaction with the pore forming unit of the inner membrane (Tim23) and the electrochemical gradient (ΔΨ) drags the presequence across the membrane. At the matrix side, the “presequence translocase-associated motor” (PAM)-complex, ropes the preprotein into the matrix by an ATP-driven mechanism that is based on the sequential interaction of mitochondrial chaperones. Next, the N-terminal sequence of the preprotein is cleaved off by the mitochondrial processing peptidase (MPP) and the protein folds within the matrix with the help of mitochondrial folding chaperones. (C)Chloroplasts. Proteins encoding a transit peptide are translated by cytosolic ribosomes and kept in an unfolded state by proteins of the Hsp70 family. Proteins of the 14-3-3 family, which bind selectively to phosphorylated transit peptides and Hsp90 proteins support the transfer to the chloroplast surface. The outer chloroplast membrane contains multi-protein complexes (TOC) that involve members of two receptor families (Toc34 and Toc159 family), a specific binding factor for Hsp90 proteins (Toc64) and the channel forming translocon Toc75. Transit peptides are translocated via sequential receptor binding from Toc34 to Toc159 and Toc75, which requires the cooperation between the GTPase domains of Toc34 and Toc159. Unfolded preproteins pass the translocon and bind to the multiprotein complex at the inner chloroplast membrane (TIC), involving the pore forming protein Tic20, Tic110, and Tic40, which allow the transfer of the transit peptide across the inner membrane. In the stroma a complex machinery of CpHsp70, Hsp90, and Hsp93, which is attached to the inner side of the chloroplast membrane by the interaction with TIC-proteins, supports the import of the preprotein by an ATPase driven mechanism. Within the chloroplast the transit peptide is cleaved off and the imported proteins are folded. (D)ER: Co-translational (left part). A functional signal peptide sequence initiates the binding of the signal recognition particle (SRP complex) upon its appearance at the ribosomal exit site. SRP binding stalls translation until the trimeric complex consisting of a nascent chain harboring a signal peptide, a ribosome and a SRP binds to the heterodimeric SRP-receptor (SR) on the surface of the ER. Subsequently, the signal peptide and the ribosome become transferred to the outer side of the Sec61 complex, which is the channel forming translocon. The release of the SRP is coupled to the resumption of translation and the newly synthesized protein is directly inserted into the lumen of the ER. This complex mechanism involves the cooperation of GTPase domains within the SRP and the SR, whereby the hydrolysis of GTP is coupled to diverse conformational changes. However, the major energy consuming step that drives the translocation of preproteins across the ER membrane is the energy of translation (GTP hydrolysis). At the inner side of the ER the signal peptide is cleaved off by the signal peptidase and the protein is folded by the help of luminal chaperones. Post-translational (right part). Proteins with N-termini that are not recognized by the SRP in spite of a functional signal peptide are translated to completion in the cytosol, but their folding is prevented by the interaction with cytosolic Hsp70 proteins. The preprotein interacts with the Sec61 complex in the ER membrane and becomes translocated across the membrane by ATP driven pulling mechanism exerted by luminal chaperones. Inside the ER the preproteins are processed by a signal peptidase (SP) and the proteins fold with the help of chaperones. Protein complexes are indicated in capital letters, proteins are indicated according to the nomenclature used in this manuscript.
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Figure 1: Protein transport routes from the cytosol into peroxisomes, mitochondria, chloroplasts, and the ER: The transport routes are depicted schematically to highlight certain players3. (A)Peroxisomes. Proteins encoding either a PTS1 or a PTS2 are folded within the cytosol and interact with the appropriated receptor proteins, Pex5 or the Pex7/co-receptor complex. This induces the translocation of cargo loaded receptors to the docking complex (DC), where they integrate into the peroxisomal membrane and release the cargo into the lumen. Finally, Pex5 and the Pex7/co-receptor complex are ubiquitylated by a specific ubiquitination machinery (UB) and recycled into the cytosol by an ATP driven extraction exerted by the receptor extraction machinery (REM). Soluble proteins reach the peroxisomal matrix in a folded state, but PTS2-carrying proteins are processed by the peroxisomal processing peptidase (PPP). (B)Mitochondria. Proteins encoding a presequence are translated within the cytosol, but remain in an unfolded state due to their association with proteins of the Hsp70 family. These complexes are transferred by the help of an additional cytosolic factor to a protein complex at the outer mitochondrial membrane (TOM), where the preprotein sequentially interacts with the receptors for soluble proteins (Tom20 and Tom22), before it is handed over to the pore forming translocon (Tom40). The preprotein crosses the outer mitochondrial membrane in an unfolded state and interacts with a protein complex in the inner mitochondrial membrane (TIM). The binding to Tim40 mediates the interaction with the pore forming unit of the inner membrane (Tim23) and the electrochemical gradient (ΔΨ) drags the presequence across the membrane. At the matrix side, the “presequence translocase-associated motor” (PAM)-complex, ropes the preprotein into the matrix by an ATP-driven mechanism that is based on the sequential interaction of mitochondrial chaperones. Next, the N-terminal sequence of the preprotein is cleaved off by the mitochondrial processing peptidase (MPP) and the protein folds within the matrix with the help of mitochondrial folding chaperones. (C)Chloroplasts. Proteins encoding a transit peptide are translated by cytosolic ribosomes and kept in an unfolded state by proteins of the Hsp70 family. Proteins of the 14-3-3 family, which bind selectively to phosphorylated transit peptides and Hsp90 proteins support the transfer to the chloroplast surface. The outer chloroplast membrane contains multi-protein complexes (TOC) that involve members of two receptor families (Toc34 and Toc159 family), a specific binding factor for Hsp90 proteins (Toc64) and the channel forming translocon Toc75. Transit peptides are translocated via sequential receptor binding from Toc34 to Toc159 and Toc75, which requires the cooperation between the GTPase domains of Toc34 and Toc159. Unfolded preproteins pass the translocon and bind to the multiprotein complex at the inner chloroplast membrane (TIC), involving the pore forming protein Tic20, Tic110, and Tic40, which allow the transfer of the transit peptide across the inner membrane. In the stroma a complex machinery of CpHsp70, Hsp90, and Hsp93, which is attached to the inner side of the chloroplast membrane by the interaction with TIC-proteins, supports the import of the preprotein by an ATPase driven mechanism. Within the chloroplast the transit peptide is cleaved off and the imported proteins are folded. (D)ER: Co-translational (left part). A functional signal peptide sequence initiates the binding of the signal recognition particle (SRP complex) upon its appearance at the ribosomal exit site. SRP binding stalls translation until the trimeric complex consisting of a nascent chain harboring a signal peptide, a ribosome and a SRP binds to the heterodimeric SRP-receptor (SR) on the surface of the ER. Subsequently, the signal peptide and the ribosome become transferred to the outer side of the Sec61 complex, which is the channel forming translocon. The release of the SRP is coupled to the resumption of translation and the newly synthesized protein is directly inserted into the lumen of the ER. This complex mechanism involves the cooperation of GTPase domains within the SRP and the SR, whereby the hydrolysis of GTP is coupled to diverse conformational changes. However, the major energy consuming step that drives the translocation of preproteins across the ER membrane is the energy of translation (GTP hydrolysis). At the inner side of the ER the signal peptide is cleaved off by the signal peptidase and the protein is folded by the help of luminal chaperones. Post-translational (right part). Proteins with N-termini that are not recognized by the SRP in spite of a functional signal peptide are translated to completion in the cytosol, but their folding is prevented by the interaction with cytosolic Hsp70 proteins. The preprotein interacts with the Sec61 complex in the ER membrane and becomes translocated across the membrane by ATP driven pulling mechanism exerted by luminal chaperones. Inside the ER the preproteins are processed by a signal peptidase (SP) and the proteins fold with the help of chaperones. Protein complexes are indicated in capital letters, proteins are indicated according to the nomenclature used in this manuscript.

Mentions: In spite of major differences between the import mechanisms of the above-mentioned organelles, the key steps are similar. Receptor proteins select suitable cargo proteins by specific interaction with targeting signals, but this selection can occur either during translation or after translation and can act either on unfolded or folded proteins (Table 1). In all cases, the receptor initiates the interaction of the cargo protein with a complex translocation machinery that can involve the receptor protein(s) itself. Moreover, all cargo proteins are translocated through pore-like structures, but this occurs either in an unfolded linear state or as fully folded protein. After transport the N-terminal sequences encoding targeting signals are processed by specific peptidases within the organelles. Each receptor protein mediates the import of many proteins, which necessitates a recycling of these receptor proteins. The targeting signals for mitochondria, chloroplasts, and the ER are encoded within N-terminal sequences with different denominations (presequence, transit sequence, and signal peptide), whereas peroxisomal targeting signals determine proteins for peroxisomes (Table 1). A comparative overview of the import mechanisms for soluble proteins into different organelles is depicted (Figure 1) and highlights the major steps of protein import. For further details of the import mechanism the readers are referred to excellent reviews that have been published elsewhere [peroxisomes (Hettema et al., 2014; Platta et al., 2014) mitochondria (Chacinska et al., 2009; Schulz et al., 2015); chloroplasts (Li and Chiu, 2010), and ER (Akopian et al., 2013; Johnson et al., 2013b)].


The similarity between N-terminal targeting signals for protein import into different organelles and its evolutionary relevance.

Kunze M, Berger J - Front Physiol (2015)

Protein transport routes from the cytosol into peroxisomes, mitochondria, chloroplasts, and the ER: The transport routes are depicted schematically to highlight certain players3. (A)Peroxisomes. Proteins encoding either a PTS1 or a PTS2 are folded within the cytosol and interact with the appropriated receptor proteins, Pex5 or the Pex7/co-receptor complex. This induces the translocation of cargo loaded receptors to the docking complex (DC), where they integrate into the peroxisomal membrane and release the cargo into the lumen. Finally, Pex5 and the Pex7/co-receptor complex are ubiquitylated by a specific ubiquitination machinery (UB) and recycled into the cytosol by an ATP driven extraction exerted by the receptor extraction machinery (REM). Soluble proteins reach the peroxisomal matrix in a folded state, but PTS2-carrying proteins are processed by the peroxisomal processing peptidase (PPP). (B)Mitochondria. Proteins encoding a presequence are translated within the cytosol, but remain in an unfolded state due to their association with proteins of the Hsp70 family. These complexes are transferred by the help of an additional cytosolic factor to a protein complex at the outer mitochondrial membrane (TOM), where the preprotein sequentially interacts with the receptors for soluble proteins (Tom20 and Tom22), before it is handed over to the pore forming translocon (Tom40). The preprotein crosses the outer mitochondrial membrane in an unfolded state and interacts with a protein complex in the inner mitochondrial membrane (TIM). The binding to Tim40 mediates the interaction with the pore forming unit of the inner membrane (Tim23) and the electrochemical gradient (ΔΨ) drags the presequence across the membrane. At the matrix side, the “presequence translocase-associated motor” (PAM)-complex, ropes the preprotein into the matrix by an ATP-driven mechanism that is based on the sequential interaction of mitochondrial chaperones. Next, the N-terminal sequence of the preprotein is cleaved off by the mitochondrial processing peptidase (MPP) and the protein folds within the matrix with the help of mitochondrial folding chaperones. (C)Chloroplasts. Proteins encoding a transit peptide are translated by cytosolic ribosomes and kept in an unfolded state by proteins of the Hsp70 family. Proteins of the 14-3-3 family, which bind selectively to phosphorylated transit peptides and Hsp90 proteins support the transfer to the chloroplast surface. The outer chloroplast membrane contains multi-protein complexes (TOC) that involve members of two receptor families (Toc34 and Toc159 family), a specific binding factor for Hsp90 proteins (Toc64) and the channel forming translocon Toc75. Transit peptides are translocated via sequential receptor binding from Toc34 to Toc159 and Toc75, which requires the cooperation between the GTPase domains of Toc34 and Toc159. Unfolded preproteins pass the translocon and bind to the multiprotein complex at the inner chloroplast membrane (TIC), involving the pore forming protein Tic20, Tic110, and Tic40, which allow the transfer of the transit peptide across the inner membrane. In the stroma a complex machinery of CpHsp70, Hsp90, and Hsp93, which is attached to the inner side of the chloroplast membrane by the interaction with TIC-proteins, supports the import of the preprotein by an ATPase driven mechanism. Within the chloroplast the transit peptide is cleaved off and the imported proteins are folded. (D)ER: Co-translational (left part). A functional signal peptide sequence initiates the binding of the signal recognition particle (SRP complex) upon its appearance at the ribosomal exit site. SRP binding stalls translation until the trimeric complex consisting of a nascent chain harboring a signal peptide, a ribosome and a SRP binds to the heterodimeric SRP-receptor (SR) on the surface of the ER. Subsequently, the signal peptide and the ribosome become transferred to the outer side of the Sec61 complex, which is the channel forming translocon. The release of the SRP is coupled to the resumption of translation and the newly synthesized protein is directly inserted into the lumen of the ER. This complex mechanism involves the cooperation of GTPase domains within the SRP and the SR, whereby the hydrolysis of GTP is coupled to diverse conformational changes. However, the major energy consuming step that drives the translocation of preproteins across the ER membrane is the energy of translation (GTP hydrolysis). At the inner side of the ER the signal peptide is cleaved off by the signal peptidase and the protein is folded by the help of luminal chaperones. Post-translational (right part). Proteins with N-termini that are not recognized by the SRP in spite of a functional signal peptide are translated to completion in the cytosol, but their folding is prevented by the interaction with cytosolic Hsp70 proteins. The preprotein interacts with the Sec61 complex in the ER membrane and becomes translocated across the membrane by ATP driven pulling mechanism exerted by luminal chaperones. Inside the ER the preproteins are processed by a signal peptidase (SP) and the proteins fold with the help of chaperones. Protein complexes are indicated in capital letters, proteins are indicated according to the nomenclature used in this manuscript.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4585086&req=5

Figure 1: Protein transport routes from the cytosol into peroxisomes, mitochondria, chloroplasts, and the ER: The transport routes are depicted schematically to highlight certain players3. (A)Peroxisomes. Proteins encoding either a PTS1 or a PTS2 are folded within the cytosol and interact with the appropriated receptor proteins, Pex5 or the Pex7/co-receptor complex. This induces the translocation of cargo loaded receptors to the docking complex (DC), where they integrate into the peroxisomal membrane and release the cargo into the lumen. Finally, Pex5 and the Pex7/co-receptor complex are ubiquitylated by a specific ubiquitination machinery (UB) and recycled into the cytosol by an ATP driven extraction exerted by the receptor extraction machinery (REM). Soluble proteins reach the peroxisomal matrix in a folded state, but PTS2-carrying proteins are processed by the peroxisomal processing peptidase (PPP). (B)Mitochondria. Proteins encoding a presequence are translated within the cytosol, but remain in an unfolded state due to their association with proteins of the Hsp70 family. These complexes are transferred by the help of an additional cytosolic factor to a protein complex at the outer mitochondrial membrane (TOM), where the preprotein sequentially interacts with the receptors for soluble proteins (Tom20 and Tom22), before it is handed over to the pore forming translocon (Tom40). The preprotein crosses the outer mitochondrial membrane in an unfolded state and interacts with a protein complex in the inner mitochondrial membrane (TIM). The binding to Tim40 mediates the interaction with the pore forming unit of the inner membrane (Tim23) and the electrochemical gradient (ΔΨ) drags the presequence across the membrane. At the matrix side, the “presequence translocase-associated motor” (PAM)-complex, ropes the preprotein into the matrix by an ATP-driven mechanism that is based on the sequential interaction of mitochondrial chaperones. Next, the N-terminal sequence of the preprotein is cleaved off by the mitochondrial processing peptidase (MPP) and the protein folds within the matrix with the help of mitochondrial folding chaperones. (C)Chloroplasts. Proteins encoding a transit peptide are translated by cytosolic ribosomes and kept in an unfolded state by proteins of the Hsp70 family. Proteins of the 14-3-3 family, which bind selectively to phosphorylated transit peptides and Hsp90 proteins support the transfer to the chloroplast surface. The outer chloroplast membrane contains multi-protein complexes (TOC) that involve members of two receptor families (Toc34 and Toc159 family), a specific binding factor for Hsp90 proteins (Toc64) and the channel forming translocon Toc75. Transit peptides are translocated via sequential receptor binding from Toc34 to Toc159 and Toc75, which requires the cooperation between the GTPase domains of Toc34 and Toc159. Unfolded preproteins pass the translocon and bind to the multiprotein complex at the inner chloroplast membrane (TIC), involving the pore forming protein Tic20, Tic110, and Tic40, which allow the transfer of the transit peptide across the inner membrane. In the stroma a complex machinery of CpHsp70, Hsp90, and Hsp93, which is attached to the inner side of the chloroplast membrane by the interaction with TIC-proteins, supports the import of the preprotein by an ATPase driven mechanism. Within the chloroplast the transit peptide is cleaved off and the imported proteins are folded. (D)ER: Co-translational (left part). A functional signal peptide sequence initiates the binding of the signal recognition particle (SRP complex) upon its appearance at the ribosomal exit site. SRP binding stalls translation until the trimeric complex consisting of a nascent chain harboring a signal peptide, a ribosome and a SRP binds to the heterodimeric SRP-receptor (SR) on the surface of the ER. Subsequently, the signal peptide and the ribosome become transferred to the outer side of the Sec61 complex, which is the channel forming translocon. The release of the SRP is coupled to the resumption of translation and the newly synthesized protein is directly inserted into the lumen of the ER. This complex mechanism involves the cooperation of GTPase domains within the SRP and the SR, whereby the hydrolysis of GTP is coupled to diverse conformational changes. However, the major energy consuming step that drives the translocation of preproteins across the ER membrane is the energy of translation (GTP hydrolysis). At the inner side of the ER the signal peptide is cleaved off by the signal peptidase and the protein is folded by the help of luminal chaperones. Post-translational (right part). Proteins with N-termini that are not recognized by the SRP in spite of a functional signal peptide are translated to completion in the cytosol, but their folding is prevented by the interaction with cytosolic Hsp70 proteins. The preprotein interacts with the Sec61 complex in the ER membrane and becomes translocated across the membrane by ATP driven pulling mechanism exerted by luminal chaperones. Inside the ER the preproteins are processed by a signal peptidase (SP) and the proteins fold with the help of chaperones. Protein complexes are indicated in capital letters, proteins are indicated according to the nomenclature used in this manuscript.
Mentions: In spite of major differences between the import mechanisms of the above-mentioned organelles, the key steps are similar. Receptor proteins select suitable cargo proteins by specific interaction with targeting signals, but this selection can occur either during translation or after translation and can act either on unfolded or folded proteins (Table 1). In all cases, the receptor initiates the interaction of the cargo protein with a complex translocation machinery that can involve the receptor protein(s) itself. Moreover, all cargo proteins are translocated through pore-like structures, but this occurs either in an unfolded linear state or as fully folded protein. After transport the N-terminal sequences encoding targeting signals are processed by specific peptidases within the organelles. Each receptor protein mediates the import of many proteins, which necessitates a recycling of these receptor proteins. The targeting signals for mitochondria, chloroplasts, and the ER are encoded within N-terminal sequences with different denominations (presequence, transit sequence, and signal peptide), whereas peroxisomal targeting signals determine proteins for peroxisomes (Table 1). A comparative overview of the import mechanisms for soluble proteins into different organelles is depicted (Figure 1) and highlights the major steps of protein import. For further details of the import mechanism the readers are referred to excellent reviews that have been published elsewhere [peroxisomes (Hettema et al., 2014; Platta et al., 2014) mitochondria (Chacinska et al., 2009; Schulz et al., 2015); chloroplasts (Li and Chiu, 2010), and ER (Akopian et al., 2013; Johnson et al., 2013b)].

Bottom Line: The structural similarity of N-terminal targeting signals poses a challenge to the specificity of protein transport, but allows the generation of ambiguous targeting signals that mediate dual targeting of proteins into different compartments.Dual targeting might represent an advantage for adaptation processes that involve a redistribution of proteins, because it circumvents the hierarchy of targeting signals.Thus, the co-existence of two equally functional import pathways into peroxisomes might reflect a balance between evolutionary constant and flexible transport routes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna Vienna, Austria.

ABSTRACT
The proper distribution of proteins between the cytosol and various membrane-bound compartments is crucial for the functionality of eukaryotic cells. This requires the cooperation between protein transport machineries that translocate diverse proteins from the cytosol into these compartments and targeting signal(s) encoded within the primary sequence of these proteins that define their cellular destination. The mechanisms exerting protein translocation differ remarkably between the compartments, but the predominant targeting signals for mitochondria, chloroplasts and the ER share the N-terminal position, an α-helical structural element and the removal from the core protein by intraorganellar cleavage. Interestingly, similar properties have been described for the peroxisomal targeting signal type 2 mediating the import of a fraction of soluble peroxisomal proteins, whereas other peroxisomal matrix proteins encode the type 1 targeting signal residing at the extreme C-terminus. The structural similarity of N-terminal targeting signals poses a challenge to the specificity of protein transport, but allows the generation of ambiguous targeting signals that mediate dual targeting of proteins into different compartments. Dual targeting might represent an advantage for adaptation processes that involve a redistribution of proteins, because it circumvents the hierarchy of targeting signals. Thus, the co-existence of two equally functional import pathways into peroxisomes might reflect a balance between evolutionary constant and flexible transport routes.

No MeSH data available.