Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Granulins (Grns) are cysteine-rich proteins derived from progranulin (Pgrn).
• Grns possess diverse roles in healing, growth, inflammation, and neurodegeneration.
• The structure-function relationship of Grns, particularly the role of disulfide bonds, is poorly understood.

Purpose of the Study:

• To investigate the role of disulfide bonds in granulin structure and function.
• To characterize the structural dynamics and biological activity of reduced granulin B (rGrnB).

Main Methods:

• Investigated the structure of fully reduced GrnB (rGrnB) using biophysical techniques.
• Assessed rGrnB's ability to activate NF-κB in human neuroblastoma cells.
• Analyzed monomer-dimer dynamics and their correlation with biological activity.

Main Results:

• Monomeric rGrnB exhibits characteristics of an intrinsically disordered protein (IDP) at low concentrations.
• rGrnB forms a concentration-dependent dimer, creating a 'fuzzy complex' without significant structural gain.
• rGrnB activates NF-κB in a concentration-dependent manner, linked to its monomer-dimer equilibrium.

Conclusions:

• Intrinsic disorder governs the conformational dynamics of reduced granulin B.
• Disulfide bonds are critical for establishing the overall structure and function of the granulin protein family.
• rGrnB's activity and dynamics provide insights into granulin involvement in cellular signaling pathways.