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Structural determinants for binary and ternary complex formation between insulin-like growth factor-I (IGF-I) and IGF
R C Baxter1, M L Bayne, M A Cascieri
1Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
The Journal of Biological Chemistry
|January 5, 1992
Summary
Structural changes in insulin-like growth factor-I (IGF-I) impact its binding to IGF-binding protein-3 (IGFBP-3) and the acid-labile subunit. Specific regions of IGF-I are critical for these complex formations.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Insulin-like growth factor-I (IGF-I) plays crucial roles in growth and metabolism.
- IGF-I circulates in the blood primarily bound to IGF-binding proteins (IGFBPs), notably IGFBP-3.
- IGFBP-3 forms a ternary complex with IGF-I and the acid-labile subunit (ALS), modulating IGF-I bioavailability.
Purpose of the Study:
- To investigate the structural regions of IGF-I responsible for binding to IGFBP-3 and the ALS.
- To elucidate how modifications in different domains of IGF-I affect the formation of binary (IGF-I/IGFBP-3) and ternary (IGF-I/IGFBP-3/ALS) complexes.
- To identify distinct functional regions within IGF-I governing protein-protein interactions.
Main Methods:
- Synthesis and characterization of various structural analogs of recombinant human IGF-I with targeted domain alterations (B, C, A, D domains).
- Assessment of the ability of these IGF-I analogs to form binary complexes with IGFBP-3 using binding assays.
- Evaluation of the capacity of IGF-I/IGFBP-3 binary complexes to subsequently bind the ALS, forming ternary complexes.
Main Results:
- Two key regions in IGF-I were identified: one crucial for IGFBP-3 binding (B-domain residues 3-4, 8-18; A-domain residues 49-51) and another distal region influencing complex formation.
- Alterations in the primary IGFBP-3 binding site led to reduced binary complex formation and consequently less ternary complex formation.
- Modifications in the D-domain or C-domain enhanced IGFBP-3 binding but impaired the subsequent binding of the ALS to the binary complex, indicating a role for these distal regions in modulating ternary complex stability.
Conclusions:
- The ALS does not directly bind IGF-I, but its interaction within the ternary complex is indirectly influenced by structural determinants on IGF-I.
- Distinct structural regions on IGF-I mediate interactions with IGFBP-3 and influence the subsequent assembly of the ternary complex with the ALS.
- Understanding these structure-function relationships is vital for comprehending IGF-I/IGFBP-3/ALS complex dynamics and potential therapeutic interventions.