The SIRT1 N-Terminal Domain as a Common Binding Interface for PPARγ Anchoring

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Insulin resistance is a major health issue linked to type 2 diabetes and obesity.
• Sirtuin 1 (SIRT1) enhances insulin sensitivity by deacetylating Peroxisome Proliferator-Activated Receptor Gamma (PPARγ).
• Understanding the SIRT1-PPARγ binding interface is crucial for developing therapies against insulin resistance.

Purpose of the Study:

• To generate and validate binding models of SIRT1 with acetylated PPARγ.
• To elucidate the structural basis of SIRT1-PPARγ interaction.
• To investigate the role of SIRT1 domains in substrate binding and activation.

Main Methods:

• In silico modeling and in vitro binding affinity assays.
• Molecular dynamics simulations.
• Analysis of SIRT1-PPARγ binding interfaces.

Main Results:

• Four experimentally supported binding models of SIRT1 with acetylated PPARγ were generated.
• The SIRT1 N-terminus domain (NTD(3HB)) and catalytic domain (CD) form the binding interface.
• SIRT1 NTD(3HB) consistently anchors PPARγ, and its removal/mutation significantly reduces binding affinity.
• SIRT1 dimerization and dissociation upon substrate binding were observed, forming a heterodimer with PPARγ.

Conclusions:

• The SIRT1 NTD(3HB) plays a critical role in anchoring PPARγ.
• These findings provide insights into SIRT1 activation mechanisms.
• The study highlights potential therapeutic strategies for insulin resistance targeting the SIRT1-PPARγ interaction.