Analysis of the sequence motifs responsible for the interactions of peroxins 14 and 5, which are involved in glycosome biogenesis in Trypanosoma brucei.
Identifieur interne : 003233 ( Main/Exploration ); précédent : 003232; suivant : 003234Analysis of the sequence motifs responsible for the interactions of peroxins 14 and 5, which are involved in glycosome biogenesis in Trypanosoma brucei.
Auteurs : Jungwoo Choe [États-Unis] ; Juliette Moyersoen ; Claudia Roach ; Tyan L. Carter ; Erkang Fan ; Paul A M. Michels ; Wim G J. HolSource :
- Biochemistry [ 0006-2960 ] ; 2003.
Descripteurs français
- KwdFr :
- Animaux, Cytosol (métabolisme), Données de séquences moléculaires, Humains, Liaison aux protéines, Maturation post-traductionnelle des protéines, Microcorps (métabolisme), Microscopie de fluorescence, Motifs d'acides aminés, Peptides (), Protéines de répression, Protéines de transport (), Protéines membranaires (), Relation dose-effet des médicaments, Récepteurs cytoplasmiques et nucléaires (), Récepteurs cytoplasmiques et nucléaires (métabolisme), Similitude de séquences d'acides aminés, Structure tertiaire des protéines, Séquence d'acides aminés, Transport de protéines, Trypanosoma brucei brucei ().
- MESH :
- métabolisme : Cytosol, Microcorps, Récepteurs cytoplasmiques et nucléaires.
- Animaux, Données de séquences moléculaires, Humains, Liaison aux protéines, Maturation post-traductionnelle des protéines, Microscopie de fluorescence, Motifs d'acides aminés, Peptides, Protéines de répression, Protéines de transport, Protéines membranaires, Relation dose-effet des médicaments, Récepteurs cytoplasmiques et nucléaires, Similitude de séquences d'acides aminés, Structure tertiaire des protéines, Séquence d'acides aminés, Transport de protéines, Trypanosoma brucei brucei.
English descriptors
- KwdEn :
- Amino Acid Motifs, Amino Acid Sequence, Animals, Carrier Proteins (chemistry), Cytosol (metabolism), Dose-Response Relationship, Drug, Humans, Membrane Proteins (chemistry), Microbodies (metabolism), Microscopy, Fluorescence, Molecular Sequence Data, Peptides (chemistry), Peroxisomal Targeting Signal 2 Receptor, Peroxisome-Targeting Signal 1 Receptor, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein Transport, Receptors, Cytoplasmic and Nuclear (chemistry), Receptors, Cytoplasmic and Nuclear (metabolism), Repressor Proteins, Sequence Homology, Amino Acid, Trypanosoma brucei brucei (chemistry).
- MESH :
- chemical , chemistry : Carrier Proteins, Membrane Proteins, Peptides, Receptors, Cytoplasmic and Nuclear.
- chemistry : Trypanosoma brucei brucei.
- metabolism : Cytosol, Microbodies, Receptors, Cytoplasmic and Nuclear.
- Amino Acid Motifs, Amino Acid Sequence, Animals, Dose-Response Relationship, Drug, Humans, Microscopy, Fluorescence, Molecular Sequence Data, Peroxisomal Targeting Signal 2 Receptor, Peroxisome-Targeting Signal 1 Receptor, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein Transport, Repressor Proteins, Sequence Homology, Amino Acid.
Abstract
Glycosome biogenesis in trypanosomatids occurs via a process that is homologous to peroxisome biogenesis in other eukaryotes. Glycosomal matrix proteins are synthesized in the cytosol and imported posttranslationally. The import process involves a series of protein-protein interactions starting by recognition of glycosomal matrix proteins by a receptor in the cytosol. Most proteins to be imported contain so-called PTS-1 or PTS-2 targeting sequences recognized by, respectively, the receptor proteins PEX5 and PEX7. PEX14, a protein associated with the peroxisomal membrane, has been identified as a component of the docking complex and a point of convergence of the PEX5- and PEX7-dependent import pathways. In this paper, the strength of the interactions between Trypanosoma brucei PEX14 and PEX5 was studied by a fluorescence assay, using (i) a panel of N-terminal regions of TbPEX14 protein variants and (ii) a series of different peptides derived from TbPEX5, each containing one of the three WXXXF/Y motifs present in this receptor protein. On the PEX14 side, the N-terminal region of TbPEX14 including residues 1-84 appeared to be responsible for TbPEX5 binding. The results from PEX14 mutants identified specific residues in the N-terminal region of TbPEX14 involved in PEX5 binding and showed that in particular hydrophobic residues F35 and F52 are critical. On the PEX5 side, 13-mer peptides incorporating the first or the third WXXXF/Y motif bind to PEX14 with an affinity in the nanomolar range. However, the second WXXXF/Y motif peptide did not show any detectable affinity. Studies using variants of second and third motif peptides suggest that the alpha-helical content of the peptides as well as the charge of a residue at position 9 in the motif may be important for PEX14 binding. Assays with 7-, 10-, 13-, and 16-mer third motif peptides showed that 16-mers and 13-mers have comparable binding affinity for PEX14, whereas 10-mers and 7-mers have about 10- and 100-fold lower affinity than the 16-mers, respectively. The low sequence identities of PEX14 and PEX5 between parasite and its human host, and the vital importance of proper glycosome biogenesis to the parasite, render these peroxins highly promising drug targets.
DOI: 10.1021/bi034248n
PubMed: 12974625
Affiliations:
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Le document en format XML
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<term>Animals</term>
<term>Carrier Proteins (chemistry)</term>
<term>Cytosol (metabolism)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Humans</term>
<term>Membrane Proteins (chemistry)</term>
<term>Microbodies (metabolism)</term>
<term>Microscopy, Fluorescence</term>
<term>Molecular Sequence Data</term>
<term>Peptides (chemistry)</term>
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<term>Peroxisome-Targeting Signal 1 Receptor</term>
<term>Protein Binding</term>
<term>Protein Processing, Post-Translational</term>
<term>Protein Structure, Tertiary</term>
<term>Protein Transport</term>
<term>Receptors, Cytoplasmic and Nuclear (chemistry)</term>
<term>Receptors, Cytoplasmic and Nuclear (metabolism)</term>
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<term>Données de séquences moléculaires</term>
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<term>Liaison aux protéines</term>
<term>Maturation post-traductionnelle des protéines</term>
<term>Microcorps (métabolisme)</term>
<term>Microscopie de fluorescence</term>
<term>Motifs d'acides aminés</term>
<term>Peptides ()</term>
<term>Protéines de répression</term>
<term>Protéines de transport ()</term>
<term>Protéines membranaires ()</term>
<term>Relation dose-effet des médicaments</term>
<term>Récepteurs cytoplasmiques et nucléaires ()</term>
<term>Récepteurs cytoplasmiques et nucléaires (métabolisme)</term>
<term>Similitude de séquences d'acides aminés</term>
<term>Structure tertiaire des protéines</term>
<term>Séquence d'acides aminés</term>
<term>Transport de protéines</term>
<term>Trypanosoma brucei brucei ()</term>
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<term>Receptors, Cytoplasmic and Nuclear</term>
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<term>Microcorps</term>
<term>Récepteurs cytoplasmiques et nucléaires</term>
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<term>Amino Acid Sequence</term>
<term>Animals</term>
<term>Dose-Response Relationship, Drug</term>
<term>Humans</term>
<term>Microscopy, Fluorescence</term>
<term>Molecular Sequence Data</term>
<term>Peroxisomal Targeting Signal 2 Receptor</term>
<term>Peroxisome-Targeting Signal 1 Receptor</term>
<term>Protein Binding</term>
<term>Protein Processing, Post-Translational</term>
<term>Protein Structure, Tertiary</term>
<term>Protein Transport</term>
<term>Repressor Proteins</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Données de séquences moléculaires</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Maturation post-traductionnelle des protéines</term>
<term>Microscopie de fluorescence</term>
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<term>Protéines de répression</term>
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<term>Relation dose-effet des médicaments</term>
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<term>Similitude de séquences d'acides aminés</term>
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<front><div type="abstract" xml:lang="en">Glycosome biogenesis in trypanosomatids occurs via a process that is homologous to peroxisome biogenesis in other eukaryotes. Glycosomal matrix proteins are synthesized in the cytosol and imported posttranslationally. The import process involves a series of protein-protein interactions starting by recognition of glycosomal matrix proteins by a receptor in the cytosol. Most proteins to be imported contain so-called PTS-1 or PTS-2 targeting sequences recognized by, respectively, the receptor proteins PEX5 and PEX7. PEX14, a protein associated with the peroxisomal membrane, has been identified as a component of the docking complex and a point of convergence of the PEX5- and PEX7-dependent import pathways. In this paper, the strength of the interactions between Trypanosoma brucei PEX14 and PEX5 was studied by a fluorescence assay, using (i) a panel of N-terminal regions of TbPEX14 protein variants and (ii) a series of different peptides derived from TbPEX5, each containing one of the three WXXXF/Y motifs present in this receptor protein. On the PEX14 side, the N-terminal region of TbPEX14 including residues 1-84 appeared to be responsible for TbPEX5 binding. The results from PEX14 mutants identified specific residues in the N-terminal region of TbPEX14 involved in PEX5 binding and showed that in particular hydrophobic residues F35 and F52 are critical. On the PEX5 side, 13-mer peptides incorporating the first or the third WXXXF/Y motif bind to PEX14 with an affinity in the nanomolar range. However, the second WXXXF/Y motif peptide did not show any detectable affinity. Studies using variants of second and third motif peptides suggest that the alpha-helical content of the peptides as well as the charge of a residue at position 9 in the motif may be important for PEX14 binding. Assays with 7-, 10-, 13-, and 16-mer third motif peptides showed that 16-mers and 13-mers have comparable binding affinity for PEX14, whereas 10-mers and 7-mers have about 10- and 100-fold lower affinity than the 16-mers, respectively. The low sequence identities of PEX14 and PEX5 between parasite and its human host, and the vital importance of proper glycosome biogenesis to the parasite, render these peroxins highly promising drug targets.</div>
</front>
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<tree><noCountry><name sortKey="Carter, Tyan L" sort="Carter, Tyan L" uniqKey="Carter T" first="Tyan L" last="Carter">Tyan L. Carter</name>
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<name sortKey="Hol, Wim G J" sort="Hol, Wim G J" uniqKey="Hol W" first="Wim G J" last="Hol">Wim G J. Hol</name>
<name sortKey="Michels, Paul A M" sort="Michels, Paul A M" uniqKey="Michels P" first="Paul A M" last="Michels">Paul A M. Michels</name>
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<country name="États-Unis"><region name="Washington (État)"><name sortKey="Choe, Jungwoo" sort="Choe, Jungwoo" uniqKey="Choe J" first="Jungwoo" last="Choe">Jungwoo Choe</name>
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