2020
DOI: 10.1021/jacs.0c06590
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An Interprotein Co–S Coordination Complex in the B12-Trafficking Pathway

Abstract: The CblC and CblD chaperones are involved in early steps in the cobalamin trafficking pathway. Cobalamin derivatives entering the cytoplasm are converted by CblC to a common cob­(II)­alamin intermediate via glutathione-dependent alkyltransferase or reductive elimination activities. Cob­(II)­alamin is subsequently converted to one of two biologically active alkylcobalamins by downstream chaperones. The function of CblD has been elusive although it is known to form a complex with CblC under certain conditions. H… Show more

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Cited by 30 publications
(43 citation statements)
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“…7 ), and the related difference spectra of UV-Vis absorption revealed a significant spectra changes centered at 268 nm from an initial linear growth to almost unchanged (Supplementary Fig. 8 ), which could be interpreted as the steady conversion of ADH to ADH ⊃ Co 3 TPS 2 complex 26 , 55 , 56 . Luminescence titration of dye-containing cage (0.1 mM Co 3 TPS 2 and PNQ ) upon the addition of ADH in EtOH/H 2 O (3:2) exhibited significant quenching of luminescent intensity at 560 nm, and the titration curve coinciding with the non-linear Hill plot (Fig.…”
Section: Resultsmentioning
confidence: 90%
“…7 ), and the related difference spectra of UV-Vis absorption revealed a significant spectra changes centered at 268 nm from an initial linear growth to almost unchanged (Supplementary Fig. 8 ), which could be interpreted as the steady conversion of ADH to ADH ⊃ Co 3 TPS 2 complex 26 , 55 , 56 . Luminescence titration of dye-containing cage (0.1 mM Co 3 TPS 2 and PNQ ) upon the addition of ADH in EtOH/H 2 O (3:2) exhibited significant quenching of luminescent intensity at 560 nm, and the titration curve coinciding with the non-linear Hill plot (Fig.…”
Section: Resultsmentioning
confidence: 90%
“…However, the weak affinity of CblD for H 2 OCbl and the slow binding kinetics render the formation of the CblC−CblD complex via this route unlikely to be physiologically relevant. 3 In contrast, CblC binds alkylcobalamins with high affinity and catalyzes their dealkylation, 40 setting up an alternative route for complex formation with CblD. Interestingly, a subset of clinical mutations in CblD decrease the rate of thiolatocob(II)alamin oxidation in the CblC−CblD complex, 48 suggesting a functional role for this reaction in trafficking.…”
Section: A Novel Interprotein Co−sulfur Coordination Complex Between ...mentioning
confidence: 99%
“…CblD forms a complex with CblC, albeit only when cob­(II)­alamin is bound (Figure C, step ix); the first 115 residues in CblD are dispensable for this interaction . Under aerobic conditions, the resulting CblC–CblD complex forms stoichiometrically, and the spectrum reveals the formation of base-off thiolatocob­(III)­alamin . The length of the Co–sulfur bond in the CblC–CblD thiolatocob­(III)­alamin complex has been estimated to be 2.57 Å by EXAFS.…”
Section: Cytoplasmic Journey Of B12 To Methionine Synthasementioning
confidence: 99%
“…Since most of these MMADHC C-terminal truncated forms lack a large portion of the NTR domain, they are likely to have impaired binding to MMACHC and function. Interestingly, the MMADHC R250X mutation, a prevalent PTC mutation associated to late-onset cblD MMA/HC disorder [ 23 ], generates an almost complete NTR domain, but it lacks the Cys261 which acts as the sulfur ligand to cbl bound to MMACHC [ 16 ]. This may help to understand the specific late-onset phenotype associated to the R250X mutation, and opens the possibility that this mutation is not completely deleterious for all MMADHC functions during early development.…”
Section: Discussionmentioning
confidence: 99%
“…MMADHC is a 296-amino acids (32.9 kDa) protein with an N-terminal disordered region (amino acids 1–107) containing a potential mitochondrial leader sequence (MLS; amino acids 1–12), and a C-terminal Nitro Reductase-like domain (NTR; amino acids 108–296) [ 7 , 12 , 15 ]. MMADHC provides a sulfur ligand to cbl bound to MMACHC [ 16 ], and the MMADHC NTR domain enhances the oxidation of cbl [ 15 ]. Genetic alterations in the MMADHC gene cause cblD-MMA, cblD-HC or cblD-MMA/HC, depending on the nature and localization of the mutation.…”
Section: Introductionmentioning
confidence: 99%