Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A resolution

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Intrinsic factor (IF) is crucial for vitamin B12 absorption in the digestive system.
• Cobalamin (Cbl), or vitamin B12, requires IF for intestinal uptake.
• Understanding the structural basis of IF-Cbl interaction is key to nutrient absorption mechanisms.

Purpose of the Study:

• To determine the high-resolution crystal structure of the intrinsic factor-cobalamin complex.
• To elucidate the binding mode of cobalamin within intrinsic factor.
• To compare the structure with other cobalamin-binding proteins and analyze factors influencing binding.

Main Methods:

• X-ray crystallography was employed to determine the structure.
• The resolution achieved was 2.6 angstroms.
• Comparative analysis with other cobalamin transport proteins was performed.

Main Results:

• The intrinsic factor-cobalamin complex adopts an alpha(6)/alpha(6) barrel fold, comprising two domains.
• Cobalamin is bound at the interface of these domains in a base-on conformation.
• The asymmetric unit contained both full-length and truncated IF molecules, with uncharged residues surrounding Cbl and an empty sixth coordination site on cobalt.
• Structural comparison with trans-cobalamin-B12 complex was detailed.

Conclusions:

• The determined structure provides a detailed molecular understanding of intrinsic factor's role in cobalamin binding.
• Analysis of the binding environment and comparison with other transporters shed light on cobalamin analogue binding and pH effects.
• The study presents a potential explanation for species-specific differences in intrinsic factor receptor interactions.