Differential Interaction of the E3 Ligase Parkin with the Proteasomal Subunit S5a and the Endocytic Protein Eps15*
Identifieur interne : 001E59 ( Main/Curation ); précédent : 001E58; suivant : 001E60Differential Interaction of the E3 Ligase Parkin with the Proteasomal Subunit S5a and the Endocytic Protein Eps15*
Auteurs : Susan S. Safadi [Canada] ; Gary S. Shaw [Canada]Source :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2009.
English descriptors
- KwdEn :
- Adaptor Proteins, Signal Transducing, Amino Acid Motifs (genetics), Amino Acid Substitution, Calcium-Binding Proteins (chemistry), Calcium-Binding Proteins (genetics), Calcium-Binding Proteins (metabolism), Humans, Intracellular Signaling Peptides and Proteins (chemistry), Intracellular Signaling Peptides and Proteins (genetics), Intracellular Signaling Peptides and Proteins (metabolism), Magnetic Resonance Spectroscopy, Mutation, Missense, Parkinsonian Disorders (enzymology), Parkinsonian Disorders (genetics), Phosphoproteins (chemistry), Phosphoproteins (genetics), Phosphoproteins (metabolism), Proteasome Endopeptidase Complex (chemistry), Proteasome Endopeptidase Complex (genetics), Proteasome Endopeptidase Complex (metabolism), Signal Transduction (genetics), Ubiquitin-Protein Ligases (chemistry), Ubiquitin-Protein Ligases (genetics), Ubiquitin-Protein Ligases (metabolism), Ubiquitination.
- MESH :
- chemical , chemistry : Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, Phosphoproteins, Proteasome Endopeptidase Complex, Ubiquitin-Protein Ligases.
- chemical , genetics : Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, Phosphoproteins, Proteasome Endopeptidase Complex, Ubiquitin-Protein Ligases.
- chemical , metabolism : Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, Phosphoproteins, Proteasome Endopeptidase Complex, Ubiquitin-Protein Ligases.
- chemical : Adaptor Proteins, Signal Transducing.
- enzymology : Parkinsonian Disorders.
- genetics : Amino Acid Motifs, Parkinsonian Disorders, Signal Transduction.
- Amino Acid Substitution, Humans, Magnetic Resonance Spectroscopy, Mutation, Missense, Ubiquitination.
Abstract
Parkin is a multidomain E3 ligase associated with autosomal recessive Parkinson disease. The N-terminal ubiquitin-like domain (Ubld) of parkin functions with the S5a proteasomal subunit, positioning substrate proteins for degradation. In addition the parkin Ubld recruits the endocytotic protein Eps15, allowing the E3 ligase to ubiquinate Eps15 distal from its parkin-interacting site. The recognition sequences in the S5a subunit and Eps15 for the parkin Ubld are ubiquitin-interacting motifs (UIM). Each protein has two UIM sequences separated by a 50-residue spacer in S5a, but only ∼5 residues in Eps15. In this work we used NMR spectroscopy to determine how the parkin Ubld recognizes the proteasomal subunit S5a compared with Eps15, a substrate for ubiquitination. We show that Eps15 contains two flexible α-helices each encompassing a UIM sequence. The α-helix surrounding UIM II is longer than that for UIM I, a situation that is reversed from S5a. Furthermore, we show the parkin Ubld preferentially binds to UIM I in the S5a subunit. This interaction is strongly diminished in a K48A substitution, found near the center of the S5a interacting surface on the parkin Ubld. In contrast to S5a, parkin recruits Eps15 using both its UIM sequences resulting in a larger interaction surface that includes residues from β1 and β2, not typically known to interact with UIM sequences. These results show that the parkin Ubld uses differential surfaces to recruit UIM regions from the S5a proteasomal subunit compared with Eps15 involved in cell signaling.
Url:
DOI: 10.1074/jbc.M109.041970
PubMed: 19875440
PubMed Central: 2801268
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PMC:2801268Le document en format XML
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<term>Amino Acid Substitution</term>
<term>Calcium-Binding Proteins (chemistry)</term>
<term>Calcium-Binding Proteins (genetics)</term>
<term>Calcium-Binding Proteins (metabolism)</term>
<term>Humans</term>
<term>Intracellular Signaling Peptides and Proteins (chemistry)</term>
<term>Intracellular Signaling Peptides and Proteins (genetics)</term>
<term>Intracellular Signaling Peptides and Proteins (metabolism)</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Mutation, Missense</term>
<term>Parkinsonian Disorders (enzymology)</term>
<term>Parkinsonian Disorders (genetics)</term>
<term>Phosphoproteins (chemistry)</term>
<term>Phosphoproteins (genetics)</term>
<term>Phosphoproteins (metabolism)</term>
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<term>Proteasome Endopeptidase Complex (genetics)</term>
<term>Proteasome Endopeptidase Complex (metabolism)</term>
<term>Signal Transduction (genetics)</term>
<term>Ubiquitin-Protein Ligases (chemistry)</term>
<term>Ubiquitin-Protein Ligases (genetics)</term>
<term>Ubiquitin-Protein Ligases (metabolism)</term>
<term>Ubiquitination</term>
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<term>Proteasome Endopeptidase Complex</term>
<term>Ubiquitin-Protein Ligases</term>
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<term>Intracellular Signaling Peptides and Proteins</term>
<term>Phosphoproteins</term>
<term>Proteasome Endopeptidase Complex</term>
<term>Ubiquitin-Protein Ligases</term>
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<term>Intracellular Signaling Peptides and Proteins</term>
<term>Phosphoproteins</term>
<term>Proteasome Endopeptidase Complex</term>
<term>Ubiquitin-Protein Ligases</term>
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<term>Parkinsonian Disorders</term>
<term>Signal Transduction</term>
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<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term>
<term>Humans</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Mutation, Missense</term>
<term>Ubiquitination</term>
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<front><div type="abstract" xml:lang="en"><p>Parkin is a multidomain E3 ligase associated with autosomal recessive Parkinson disease. The N-terminal ubiquitin-like domain (Ubld) of parkin functions with the S5a proteasomal subunit, positioning substrate proteins for degradation. In addition the parkin Ubld recruits the endocytotic protein Eps15, allowing the E3 ligase to ubiquinate Eps15 distal from its parkin-interacting site. The recognition sequences in the S5a subunit and Eps15 for the parkin Ubld are ubiquitin-interacting motifs (UIM). Each protein has two UIM sequences separated by a 50-residue spacer in S5a, but only ∼5 residues in Eps15. In this work we used NMR spectroscopy to determine how the parkin Ubld recognizes the proteasomal subunit S5a compared with Eps15, a substrate for ubiquitination. We show that Eps15 contains two flexible α-helices each encompassing a UIM sequence. The α-helix surrounding UIM II is longer than that for UIM I, a situation that is reversed from S5a. Furthermore, we show the parkin Ubld preferentially binds to UIM I in the S5a subunit. This interaction is strongly diminished in a K48A substitution, found near the center of the S5a interacting surface on the parkin Ubld. In contrast to S5a, parkin recruits Eps15 using both its UIM sequences resulting in a larger interaction surface that includes residues from β1 and β2, not typically known to interact with UIM sequences. These results show that the parkin Ubld uses differential surfaces to recruit UIM regions from the S5a proteasomal subunit compared with Eps15 involved in cell signaling.</p>
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