Are granulins copper sequestering proteins?

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Granulins (GRNs) are cysteine-rich peptides derived from progranulin (PGRN).
• GRNs and PGRN are implicated in neurodegenerative diseases and possess redox-sensitive properties.
• Previous work indicated GRN-3 and GRN-5 are disordered in their reduced state.

Purpose of the Study:

• To investigate the metal-binding properties of reduced GRN-3 and GRN-5.
• To determine if GRNs play a role in metal sequestration and homeostasis.
• To explore the potential of GRNs in mitigating copper-induced oxidative stress.

Main Methods:

• Tested metal binding propensity of reduced GRN-3 and GRN-5.
• Utilized neutral and acidic pH conditions to mimic cytosolic and lysosomal environments.
• Analyzed structural changes and multimerization upon metal binding.

Main Results:

• GRN-3 and GRN-5 selectively bind copper (Cu) at neutral pH, with a preference for Cu(I).
• Copper binding did not induce a disorder-to-order transition but caused partial GRN multimerization.
• GRNs exhibit high-affinity copper sequestration in the picomolar range.

Conclusions:

• GRN-3 and GRN-5 possess significant copper-binding capabilities, comparable to known copper-sequestering proteins.
• GRNs may contribute to cellular copper homeostasis and reduce copper-induced oxidative stress.
• This study reveals the novel metal-coordinating properties of granulin peptides, impacting their function in disease.