Structural Basis for the Activation of IKK1/α

Area of Science:

• Molecular biology
• Structural biology
• Cell signaling

Background:

• The NF-κB family of transcription factors regulates critical cellular processes.
• Distinct signaling pathways, canonical and non-canonical, activate NF-κB.
• The molecular mechanisms differentiating IκB kinase 1 (IKK1) and IκB kinase 2 (IKK2) are not fully understood.

Purpose of the Study:

• To elucidate the structural and biochemical basis for the distinct signaling roles of IKK1 and IKK2.
• To investigate the quaternary structures of human IKK1.

Main Methods:

• Single-particle cryoelectron microscopy (cryo-EM) to determine structures in solution.
• X-ray crystallography to determine high-resolution structures.
• Biochemical assays to assess protein function.

Main Results:

• Human IKK1 exists in both dimeric and hexameric forms.
• The hexameric form, a trimer of dimers, is observed in crystals but rare in solution.
• A specific surface involved in hexamer formation is essential for IKK1's role in non-canonical NF-κB signaling (p100 to p52 processing).
• This surface significantly differs from the corresponding surface in IKK2.

Conclusions:

• IKK1 utilizes a distinct structural surface for non-canonical NF-κB pathway signaling.
• This divergence in surface structure likely underlies the differential signaling activities of IKK1 and IKK2.
• Structural insights provide a foundation for understanding distinct NF-κB pathway activation.