MG53-IRS-1 (Mitsugumin 53-Insulin Receptor Substrate-1) Interaction Disruptor Sensitizes Insulin Signaling in Skeletal Muscle.
J Biol Chem
; 291(52): 26627-26635, 2016 Dec 23.
Article
in En
| MEDLINE
| ID: mdl-27810898
ABSTRACT
Mitsugumin 53 (MG53) is an E3 ligase that interacts with and ubiquitinates insulin receptor substrate-1 (IRS-1) in skeletal muscle; thus, an MG53-IRS-1 interaction disruptor (MID), which potentially sensitizes insulin signaling with an elevated level of IRS-1 in skeletal muscle, is an excellent candidate for treating insulin resistance. To screen for an MID, we developed a bimolecular luminescence complementation system using an N-terminal luciferase fragment fused with IRS-1 and a C-terminal luciferase fragment fused with an MG53 C14A mutant that binds to IRS-1 but does not have E3 ligase activity. An MID, which was discovered using the bimolecular luminescence complementation system, disrupted the molecular association of MG53 with IRS-1, thus abolishing MG53-mediated IRS-1 ubiquitination and degradation. Thus, the MID sensitized insulin signaling and increased insulin-elicited glucose uptake with an elevated level of IRS-1 in C2C12 myotubes. These data indicate that this MID holds promise as a drug candidate for treating insulin resistance.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Transcription Factors
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Nuclear Proteins
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Carrier Proteins
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Muscle, Skeletal
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Small Molecule Libraries
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Insulin Receptor Substrate Proteins
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Protein Interaction Maps
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Insulin
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Microtubule Proteins
Limits:
Humans
Language:
En
Year:
2016
Type:
Article