An unusual Co-S bond links B₁₂ chaperones in an interprotein complex

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Chaperones are crucial for specific transition metal loading and preventing side reactions in cellular pathways.
• Vitamin B12 (cobalamin) is an essential human cofactor requiring specific translocation mechanisms due to its complex structure.

Purpose of the Study:

• To determine the crystal structure of human MMACHC and MMADHC B12 chaperones.
• To elucidate the mechanism of B12 translocation and protection mediated by these chaperones.

Main Methods:

• X-ray crystallography at 3.4 Å resolution.
• Analysis of the interprotein complex structure and B12 binding site.

Main Results:

• The crystal structure reveals MMACHC and MMADHC tethered by a covalent cobalt-sulfur bond.
• Vitamin B12 is bound to MMACHC in a base-off state, with MMADHC providing an axial ligand.
• The complex prevents spontaneous decomposition of B12 derivatives, suggesting a protective role.

Conclusions:

• The covalent cobalt-sulfur bond is essential for high-affinity complex formation between MMACHC and MMADHC.
• The interprotein complex likely facilitates B12 exit from the chaperones.
• The interface is not associated with known clinical variants, highlighting the importance of the cobalt-sulfur bond.