ArticleThe Journal of biological chemistry2015
Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- Clinical, phenotypic and genetic landscape of case reports with genetically proven inherited disorders of vitamin BCell reports. Medicine · 2022Pooled it
- Structural insights into cobalamin loading and reactivation of human methionine synthase.Nature communications · 2026Article
- Late-onset epi-cblC methylmalonic aciduria with tissue-variable MMACHC promoter methylation due to a stop retained PRDX1 variant.Clinical epigenetics · 2026Article
- The Role of Cobalamin in Multiple Sclerosis: An Update.Inflammation · 2025Review
- Vitamin BInternational journal of molecular sciences · 2024Review
- Vitamin BAnimals : an open access journal from MDPI · 2024Article
- Vitamin B12 Deficiency and the Nervous System: Beyond Metabolic Decompensation-Comparing Biological Models and Gaining New Insights into Molecular and Cellular Mechanisms.International journal of molecular sciences · 2024Review
- Interaction of Glutathione with MMACHC Arginine-Rich Pocket Variants Associated with Cobalamin C Disease: Insights from Molecular Modeling.Biomedicines · 2023Article
- Cobalt-Sulfur Coordination Chemistry Drives BJournal of the American Chemical Society · 2023Article
- Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease.iScience · 2022Review
- Article
- Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.Nature communications · 2022Article
- Acute Lymphoblastic Leukemia in Combined Methylmalonic Acidemia and Homocysteinemia (cblC Type): A Case Report and Literature Review.Frontiers in genetics · 2022Article
- Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia.International journal of molecular sciences · 2021Article
- MMADHC premature termination codons in the pathogenesis of cobalamin D disorder: Potential of translational readthrough reconstitution.Molecular genetics and metabolism reports · 2021Article
- When to measure plasma homocysteine and how to place it in context: The homocystinurias.Journal of mother and child · 2020Review
- An Interprotein Co-S Coordination Complex in the BJournal of the American Chemical Society · 2020Article
- The role of HCFC1 in syndromic and non-syndromic intellectual disability.Medical research archives · 2020Article
- Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin BThe Journal of biological chemistry · 2017Article
- From structural biology to designing therapy for inborn errors of metabolism.Journal of inherited metabolic disease · 2016Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.