A solution structure analysis reveals a bent collagen triple helix in the complement activation recognition molecule...

Area of Science:

• Biochemistry
• Structural Biology
• Immunology

Background:

• Mannan-binding lectin (MBL) utilizes collagen triple helices for complement activation.
• Mutations in MBL collagen regions are linked to common immunodeficiencies.
• Understanding MBL collagen structure is vital for complement pathway function.

Purpose of the Study:

• To investigate the solution structures of MBL-like collagen peptides.
• To evaluate the impact of sequence variations, including GQG interruptions, on collagen triple helix structure and stability.
• To compare experimental data with computational models.

Main Methods:

• Analytical ultracentrifugation
• Small-angle X-ray and neutron scattering
• Molecular dynamics simulations
• Analysis of MBL-like and control collagen peptides

Main Results:

• MBL-like collagen peptides, particularly those with a GQG interruption, exhibited significant bending (up to 85°).
• The GQG interruption reduced thermal stability compared to standard collagen peptides.
• Collagen triple helix linearity is sequence-dependent, with MBL peptides showing pronounced flexibility and bending.
• Benchmark peptides (POG)n were more linear but retained conformational flexibility.

Conclusions:

• The collagen triple helix is conformationally flexible and not strictly linear.
• Sequence variations, such as the GQG interruption in MBL, dictate the degree of bending and flexibility.
• The observed bend in MBL GQG peptides may play a critical role in lectin pathway activation, similar to complement C1q.
• Structural insights into MBL collagen could inform strategies for managing complement-related immunodeficiencies.