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Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking.

  • Froese DS From the Division of Metabolism and Children's Research Center, University Children's, Hospital, CH-8032 Zurich, Switzerland, radiz - Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, CH-8032 Zurich, Switzerland.
  • Kopec J the Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
  • Fitzpatrick F the Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
  • Schuller M the Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
  • McCorvie TJ the Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
  • Chalk R the Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
  • Plessl T From the Division of Metabolism and Children's Research Center, University Children's, Hospital, CH-8032 Zurich, Switzerland.
  • Fettelschoss V From the Division of Metabolism and Children's Research Center, University Children's, Hospital, CH-8032 Zurich, Switzerland.
  • Fowler B From the Division of Metabolism and Children's Research Center, University Children's, Hospital, CH-8032 Zurich, Switzerland.
  • Baumgartner MR From the Division of Metabolism and Children's Research Center, University Children's, Hospital, CH-8032 Zurich, Switzerland, radiz - Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, CH-8032 Zurich, Switzerland, the Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zurich, Switzerland matthias.baumgartner@kispi.uzh.ch.
  • Yue WW the Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom, and wyatt.yue@sgc.ox.ac.uk.
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  • 2015-10-21
Published in:
  • The Journal of biological chemistry. - 2015
crystal structure
metabolic disease
nitroreductase fold
protein-protein interaction
site-directed mutagenesis
small-angle x-ray scattering (SAXS)
vitamin B12
Amino Acid Sequence
Animals
Binding Sites
Carrier Proteins
Crystallography, X-Ray
Humans
Intracellular Signaling Peptides and Proteins
Metabolic Diseases
Mice
Mitochondrial Membrane Transport Proteins
Molecular Chaperones
Molecular Sequence Data
Mutagenesis, Site-Directed
Mutation
Nitroreductases
Oxidoreductases
Phenotype
Protein Binding
Protein Interaction Mapping
Protein Multimerization
Protein Structure, Secondary
Protein Transport
Recombinant Proteins
Sequence Homology, Amino Acid
Vitamin B 12
English Conversion of vitamin B12 (cobalamin, Cbl) into the cofactor forms methyl-Cbl (MeCbl) and adenosyl-Cbl (AdoCbl) is required for the function of two crucial enzymes, mitochondrial methylmalonyl-CoA mutase and cytosolic methionine synthase, respectively. The intracellular proteins MMACHC and MMADHC play important roles in processing and targeting the Cbl cofactor to its destination enzymes, and recent evidence suggests that they may interact while performing these essential trafficking functions. To better understand the molecular basis of this interaction, we have mapped the crucial protein regions required, indicate that Cbl is likely processed by MMACHC prior to interaction with MMADHC, and identify patient mutations on both proteins that interfere with complex formation, via different mechanisms. We further report the crystal structure of the MMADHC C-terminal region at 2.2 Å resolution, revealing a modified nitroreductase fold with surprising homology to MMACHC despite their poor sequence conservation. Because MMADHC demonstrates no known enzymatic activity, we propose it as the first protein known to repurpose the nitroreductase fold solely for protein-protein interaction. Using small angle x-ray scattering, we reveal the MMACHC-MMADHC complex as a 1:1 heterodimer and provide a structural model of this interaction, where the interaction region overlaps with the MMACHC-Cbl binding site. Together, our findings provide novel structural evidence and mechanistic insight into an essential biological process, whereby an intracellular "trafficking chaperone" highly specific for a trace element cofactor functions via protein-protein interaction, which is disrupted by inherited disease mutations.
Language
  • English
Open access status
hybrid
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Persistent URL
https://sonar.ch/global/documents/81414
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