Insulin-like growth factor binding protein-3: factors affecting binary and ternary complex formation

Area of Science:

• Endocrinology
• Protein biochemistry

Background:

• IGFBP-3 is the primary serum carrier for IGF-I and IGF-II in adults.
• IGFBP-3 typically circulates in a ternary complex with IGF and the acid-labile subunit (ALS).
• Previous studies lacked data on IGFBP-3 complex affinities under physiological conditions.

Purpose of the Study:

• To determine the binding affinities of IGF and ALS to IGFBP-3 under physiologically relevant conditions.
• To elucidate the influence of pH, ionic strength, and temperature on these interactions.

Main Methods:

• Investigated IGF-I, IGF-II, and ALS binding to IGFBP-3.
• Assessed binding affinities across a range of pH values (4.0-7.4).
• Evaluated the effects of NaCl concentration and temperature (22°C vs. 37°C) on binding.

Main Results:

• IGF-I and IGF-II binding to IGFBP-3 was optimal at pH 4.0-5.5, with reduced affinity at pH 7.4.
• ALS binding peaked at pH 5.5-6.0 and was significantly reduced at pH 7.4 and 37°C.
• Under physiological conditions, ALS binding affinities were 300-fold (IGF-I) and 2000-fold (IGF-II) lower than binary complex formation constants.

Conclusions:

• IGFBP-3 binding affinities for IGF-I and IGF-II are highly pH-dependent.
• ALS binding to IGFBP-3 complexes is considerably weaker under physiological conditions than previously estimated.
• ALS dissociation is a critical regulatory mechanism controlling IGF bioavailability.