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

Abstract

Chaperones in trafficking pathways ensure specificity of transition metal loading and protection against adventitious side reactions. In B₁₂, an essential cofactor for humans, a cobalt ion is coordinated to a >1.3 kDa tetrapyrrolic scaffold, posing logistical challenges for its translocation. In this study, we report the 3.4 Å crystal structure of the human MMACHC and MMADHC B₁₂ chaperones, tethered via a rarely seen covalent cobalt-sulfur bond. B₁₂ is bound in the base-off state to MMACHC, with Cys-261 on MMADHC serving as the upper axial ligand; the lower-axial position is vacant. The propensity of thiolato-cobalamin derivatives bound to MMACHC to undergo spontaneous decomposition via general acid catalysis or reduction/oxidation chemistry is averted in the interprotein complex with MMADHC. An exposed face in the complex suggests an exit route for B₁₂. No known clinical variants localize to the interprotein interface, consistent with the cobalt-sulfur bond being key to forming the high-affinity complex.