5A4R

Crystal structure of a vitamin B12 trafficking protein

Summary for 5A4R

• Entry DOI: 10.2210/pdb5a4r/pdb
• Descriptor: METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA TYPE D HOMOLOG, MITOCHONDRIAL (2 entities in total)
• Functional Keywords: transport protein
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Cellular location: Cytoplasm : Q99LS1
• Total number of polymer chains: 1
• Total formula weight: 19215.60

Authors

Kopec, J.,Fitzpatrick, F.,Froese, D.S.,Velupillai, S.,Nowak, R.,Chalk, R.,Burgess-Brown, N.,von Delft, F.,Arrowsmith, C.,Edwards, A.,Bountra, C.,Fowler, B.,Baumgartner, M.R.,Yue, W.W. (deposition date: 2015-06-11, release date: 2015-10-28, Last modification date: 2024-05-08)

Primary citation

Froese, D.S.,Kopec, J.,Fitzpatrick, F.,Schuller, M.,Mccorvie, T.J.,Chalk, R.,Plessl, T.,Fettelschoss, V.,Fowler, B.,Baumgartner, M.R.,Yue, W.W.
Structural Insights Into the Mmachc-Mmadhc Protein Complex Involved in Vitamin B12 Trafficking.
J.Biol.Chem., 290:29167-, 2015

PubMed 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.

PubMed: 26483544
DOI: 10.1074/JBC.M115.683268

Experimental method

X-RAY DIFFRACTION (2.25 Å)