Modulation of conformational features and oligomerization of MMACHC by cobalamin variants: impact of the R161Q mutation in cblC disease.
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| Title: | Modulation of conformational features and oligomerization of MMACHC by cobalamin variants: impact of the R161Q mutation in cblC disease. |
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| Authors: | Longo, Lisa1,2 (AUTHOR), Costa, Maria Assunta1 (AUTHOR), Carrotta, Rita1 (AUTHOR), Mangione, Maria Rosalia1 (AUTHOR), Martorana, Vincenzo1 (AUTHOR), Tutone, Marco2 (AUTHOR), Ortore, Maria Grazia3 (AUTHOR), Garcia-Franco, Paula M.4,5 (AUTHOR), Vega, Sonia4 (AUTHOR), Velazquez-Campoy, Adrian4,6,7,8 (AUTHOR) adrianvc@unizar.es, Passantino, Rosa1 (AUTHOR) rosa.passantino@cnr.it, Vilasi, Silvia1 (AUTHOR) silvia.vilasi@cnr.it |
| Source: | European Biophysics Journal. Jun2026, Vol. 55 Issue 3, p427-438. 12p. |
| Subjects: | Vitamin B12, Genetic mutation, Isothermal titration calorimetry, Circular dichroism, Vitamin B12 deficiency, Protein subunits |
| Abstract: | Vitamin B12 (cobalamin, Cbl) is a coordination compound of the cobalt, located at the center of a corrin ring composed of four pyrrolic-like groups. The cobalt ion can be bound to a variety of upper axial ligands, which vary among different cobalamin forms, including hydroxocobalamin (OHCbl), cyanocobalamin (CNCbl), methylcobalamin (MeCbl), and adenosylcobalamin (AdoCbl). MeCbl and AdoCbl are considered the biologically active forms, serving as cofactors in the metabolism of methylmalonic acid (MMA) and homocysteine (HCY). Impaired conversion of these metabolites leads to their pathological accumulation, resulting in severe cellular damage. This is precisely what occurs in cblC deficiency, a rare inborn disorder caused by mutations in the MMACHC protein, which plays a crucial role in binding and processing the various cobalamin forms. Mutations affecting MMACHC function impair its ability to correctly handle cobalamins, leading to the disease. In this study, we evaluated the impact of various cobalamin forms, specifically AdoCbl, MeCbl, and CNCbl, on the stability and oligomeric organization of the wild type MMACHC protein, using circular dichroism spectroscopy, native gel electrophoresis, and small-angle X-ray scattering. Moreover, isothermal titration calorimetry experiments provided insights into the thermodynamic parameters governing MMACHC binding to these cobalamins. In addition, we also assessed how the R161Q mutation in MMACHC alters the affinity of this protein for the different vitamin B12 forms, leading to decreased stability and impaired homodimerization, a process likely relevant to its functional role. Our findings provide molecular insights into cblC pathogenesis and advance our understanding of MMACHC structure–function relationships. [ABSTRACT FROM AUTHOR] |
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| Database: | Engineering Source |
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| Abstract: | Vitamin B12 (cobalamin, Cbl) is a coordination compound of the cobalt, located at the center of a corrin ring composed of four pyrrolic-like groups. The cobalt ion can be bound to a variety of upper axial ligands, which vary among different cobalamin forms, including hydroxocobalamin (OHCbl), cyanocobalamin (CNCbl), methylcobalamin (MeCbl), and adenosylcobalamin (AdoCbl). MeCbl and AdoCbl are considered the biologically active forms, serving as cofactors in the metabolism of methylmalonic acid (MMA) and homocysteine (HCY). Impaired conversion of these metabolites leads to their pathological accumulation, resulting in severe cellular damage. This is precisely what occurs in cblC deficiency, a rare inborn disorder caused by mutations in the MMACHC protein, which plays a crucial role in binding and processing the various cobalamin forms. Mutations affecting MMACHC function impair its ability to correctly handle cobalamins, leading to the disease. In this study, we evaluated the impact of various cobalamin forms, specifically AdoCbl, MeCbl, and CNCbl, on the stability and oligomeric organization of the wild type MMACHC protein, using circular dichroism spectroscopy, native gel electrophoresis, and small-angle X-ray scattering. Moreover, isothermal titration calorimetry experiments provided insights into the thermodynamic parameters governing MMACHC binding to these cobalamins. In addition, we also assessed how the R161Q mutation in MMACHC alters the affinity of this protein for the different vitamin B12 forms, leading to decreased stability and impaired homodimerization, a process likely relevant to its functional role. Our findings provide molecular insights into cblC pathogenesis and advance our understanding of MMACHC structure–function relationships. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 01757571 |
| DOI: | 10.1007/s00249-025-01777-5 |
