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Structure of MMACHC reveals an arginine-rich pocket and a domain-swapped dimer for its B12 processing function.

Froese DS, Krojer T, Wu X, Shrestha R, Kiyani W, von Delft F, Gravel RA, Oppermann U, Yue WW
Biochemistry 51 5083-90 (2012)
Cited: 27 times
EuropePMC logo PMID: 22642810

Abstract

Defects in the MMACHC gene represent the most common disorder of cobalamin (Cbl) metabolism, affecting synthesis of the enzyme cofactors adenosyl-Cbl and methyl-Cbl. The encoded MMACHC protein binds intracellular Cbl derivatives with different upper axial ligands and exhibits flavin mononucleotide (FMN)-dependent decyanase activity toward cyano-Cbl as well as glutathione (GSH)-dependent dealkylase activity toward alkyl-Cbls. We determined the structure of human MMACHC·adenosyl-Cbl complex, revealing a tailor-made nitroreductase scaffold which binds adenosyl-Cbl in a "base-off, five-coordinate" configuration for catalysis. We further identified an arginine-rich pocket close to the Cbl binding site responsible for GSH binding and dealkylation activity. Mutation of these highly conserved arginines, including a replication of the prevalent MMACHC missense mutation, Arg161Gln, disrupts GSH binding and dealkylation. We further showed that two Cbl-binding monomers dimerize to mediate the reciprocal exchange of a conserved "PNRRP" loop from both subunits, serving as a protein cap for the upper axial ligand in trans and required for proper dealkylation activity. Our dimeric structure is supported by solution studies, where dimerization is triggered upon binding its substrate adenosyl-Cbl or cofactor FMN. Together our data provide a structural framework to understanding catalytic function and disease mechanism for this multifunctional enzyme.

Reviews - 3som mentioned but not cited (3)

  1. Exploring the spatial and temporal organization of a cell's proteome. Beck M, Topf M, Frazier Z, Tjong H, Xu M, Zhang S, Alber F. J Struct Biol 173 483-496 (2011)
  2. From structural biology to designing therapy for inborn errors of metabolism. Yue WW. J. Inherit. Metab. Dis. 39 489-498 (2016)
  3. Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease. Esser AJ, Mukherjee S, Dereven'kov IA, Makarov SV, Jacobsen DW, Spiekerkoetter U, Hannibal L. iScience 25 104981 (2022)

Articles - 3som mentioned but not cited (3)

  1. Pathogenic mutations differentially affect the catalytic activities of the human B12-processing chaperone CblC and increase futile redox cycling. Gherasim C, Ruetz M, Li Z, Hudolin S, Banerjee R. J. Biol. Chem. 290 11393-11402 (2015)
  2. Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking. Froese DS, Kopec J, Fitzpatrick F, Schuller M, McCorvie TJ, Chalk R, Plessl T, Fettelschoss V, Fowler B, Baumgartner MR, Yue WW. J. Biol. Chem. 290 29167-29177 (2015)
  3. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Reviews citing this publication (1)

  1. Navigating the B(12) road: assimilation, delivery, and disorders of cobalamin. Gherasim C, Lofgren M, Banerjee R. J. Biol. Chem. 288 13186-13193 (2013)

Articles citing this publication (20)

  1. Structural basis for organohalide respiration. Bommer M, Kunze C, Fesseler J, Schubert T, Diekert G, Dobbek H. Science 346 455-458 (2014)
  2. Glutathione-dependent one-electron transfer reactions catalyzed by a B₁₂ trafficking protein. Li Z, Gherasim C, Lesniak NA, Banerjee R. J. Biol. Chem. 289 16487-16497 (2014)
  3. Molecular basis of cobalamin-dependent RNA modification. Dowling DP, Miles ZD, Köhrer C, Maiocco SJ, Elliott SJ, Bandarian V, Drennan CL. Nucleic Acids Res. 44 9965-9976 (2016)
  4. Ophthalmic Manifestations and Long-Term Visual Outcomes in Patients with Cobalamin C Deficiency. Brooks BP, Thompson AH, Sloan JL, Manoli I, Carrillo-Carrasco N, Zein WM, Venditti CP. Ophthalmology 123 571-582 (2016)
  5. Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia. Fofou-Caillierez MB, Mrabet NT, Chéry C, Dreumont N, Flayac J, Pupavac M, Paoli J, Alberto JM, Coelho D, Camadro JM, Feillet F, Watkins D, Fowler B, Rosenblatt DS, Guéant JL. Hum. Mol. Genet. 22 4591-4601 (2013)
  6. Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type. Backe PH, Ytre-Arne M, Røhr AK, Brodtkorb E, Fowler B, Rootwelt H, Bjørås M, Mørkrid L. JIMD Rep 11 79-85 (2013)
  7. Antivitamin B12 Inhibition of the Human B12 -Processing Enzyme CblC: Crystal Structure of an Inactive Ternary Complex with Glutathione as the Cosubstrate. Ruetz M, Shanmuganathan A, Gherasim C, Karasik A, Salchner R, Kieninger C, Wurst K, Banerjee R, Koutmos M, Kräutler B. Angew. Chem. Int. Ed. Engl. 56 7387-7392 (2017)
  8. C-terminal truncation of a bovine B(12) trafficking chaperone enhances the sensitivity of the glutathione-regulated thermostability. Jeong J, Park J, Lee DY, Kim J. BMB Rep 46 169-174 (2013)
  9. Redox-Linked Coordination Chemistry Directs Vitamin B12 Trafficking. Banerjee R, Gouda H, Pillay S. Acc Chem Res 54 2003-2013 (2021)
  10. Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases. Yamada K, Gherasim C, Banerjee R, Koutmos M. J. Biol. Chem. 290 29155-29166 (2015)
  11. An Interprotein Co-S Coordination Complex in the B12-Trafficking Pathway. Li Z, Mascarenhas R, Twahir UT, Kallon A, Deb A, Yaw M, Penner-Hahn J, Koutmos M, Warncke K, Banerjee R. J Am Chem Soc 142 16334-16345 (2020)
  12. Coordination chemistry controls the thiol oxidase activity of the B12-trafficking protein CblC. Li Z, Shanmuganathan A, Ruetz M, Yamada K, Lesniak NA, Kräutler B, Brunold TC, Koutmos M, Banerjee R. J. Biol. Chem. 292 9733-9744 (2017)
  13. Milder clinical and biochemical phenotypes associated with the c.482G>A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening. Almannai M, Marom R, Divin K, Scaglia F, Sutton VR, Craigen WJ, Lee B, Burrage LC, Graham BH. Mol. Genet. Metab. 122 60-66 (2017)
  14. PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations. Cavicchi C, Oussalah A, Falliano S, Ferri L, Gozzini A, Gasperini S, Motta S, Rigoldi M, Parenti G, Tummolo A, Meli C, Menni F, Furlan F, Daniotti M, Malvagia S, la Marca G, Chery C, Morange PE, Tregouet D, Donati MA, Guerrini R, Guéant JL, Morrone A. Clin Epigenetics 13 137 (2021)
  15. The role of HCFC1 in syndromic and non-syndromic intellectual disability. Castro VL, Quintana AM. Med Res Arch 8 (2020)
  16. Interaction of Glutathione with MMACHC Arginine-Rich Pocket Variants Associated with Cobalamin C Disease: Insights from Molecular Modeling. Antony P, Baby B, Ali A, Vijayan R, Al Jasmi F. Biomedicines 11 3217 (2023)
  17. Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type. Chern T, Achilleos A, Tong X, Hsu CW, Wong L, Poché RA. Dev Biol 468 1-13 (2020)
  18. Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy. Chern T, Achilleos A, Tong X, Hill MC, Saltzman AB, Reineke LC, Chaudhury A, Dasgupta SK, Redhead Y, Watkins D, Neilson JR, Thiagarajan P, Green JBA, Malovannaya A, Martin JF, Rosenblatt DS, Poché RA. Nat Commun 13 134 (2022)
  19. Substrate-mediated control of the conformation of an ancillary domain delivers a competent catalytic site for N-acetylneuraminic acid synthase. Joseph DD, Jiao W, Kessans SA, Parker EJ. Proteins 82 2054-2066 (2014)
  20. Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort. Wu SN, E HS, Yu Y, Ling SY, Liang LL, Qiu WJ, Zhang HW, Shuai RX, Wei HY, Yang CJ, Xu P, Chen XG, Zou H, Feng JZ, Niu TT, Hu HL, Zhang KC, Lu DY, Gong ZW, Zhan X, Ji WJ, Gu XF, Chen YX, Han LS. World J Pediatr (2023)


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