Calcium Binds to Transthyretin with Low Affinity.

Area of Science:

• Biochemistry
• Structural Biology
• Medical Biochemistry

Background:

• Transthyretin (TTR) transports thyroid hormones and retinol.
• TTR aggregation causes systemic (ATTR) amyloidosis, a common protein misfolding disease.
• The role of calcium ions (Ca2+) in TTR structure and aggregation is debated.

Purpose of the Study:

• To investigate calcium binding to TTR using high-resolution NMR spectroscopy.
• To assess the impact of calcium binding on TTR aggregation propensity at physiological pH.

Main Methods:

• High-resolution Nuclear Magnetic Resonance (NMR) spectroscopy to study Ca2+-TTR interactions.
• Assessment of TTR aggregation using mechano-enzymatic assays at physiological pH.

Main Results:

• NMR revealed labile Ca2+ interactions with TTR, leaving the native structure largely unaltered.
• Calcium binding increases TTR susceptibility to proteolytic cleavage, promoting aggregation at physiological pH.
• Approximately 7% of circulating TTR may be Ca2+-bound in vivo, increasing its aggregation risk.

Conclusions:

• Weak Ca2+ binding to TTR can enhance its aggregation propensity.
• This interaction, even in a small fraction of TTR, may be relevant for the slow development of ATTR.
• Findings provide insights into TTR's role in amyloidosis pathogenesis.