A novel function of <i>Mycobacterium tuberculosis</i> chaperonin paralog GroEL1 in copper homeostasis

Ansari, Mohammed Yousuf; Batra, Sakshi; Ojha, Hina; Dhiman, Kanika; Ganguly, Ashish; Tyagi, Jaya Sivaswami; Mande, Shekhar C.

doi:10.1002/1873-3468.13906

Cited by 12 publications

(7 citation statements)

References 61 publications

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“…The mycobacterial GroEL1 histidine-rich protein exists only as a monomer, even in the presence of stabilizers of oligomeric forms. , It has been discovered that Cu(II) induces a response of the mycobacterial GroEL1 (M. tuberculosis) and its histidine-rich C-terminal region plays an essential role in this process . The histidine-rich motif is responsible for metal ion trafficking in a variety of organisms, including bacteria. − It was predicted that proteins containing such specific sequences may be used as a molecular target for a new generation of medicines .…”

Section: Introductionmentioning

confidence: 99%

Histidine-Rich C-Terminal Tail of Mycobacterial GroEL1 and Its Copper Complex─The Impact of Point Mutations

et al. 2023

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The mycobacterial histidine-rich GroEL1 protein differs significantly compared to the well-known methionine/glycine-rich GroEL chaperonin. It was predicted that mycobacterial GroEL1 can play a significant role in the metal homeostasis of Mycobacteria but not, as its analogue, in protein folding. In this paper, we present the properties of the GroEL1 His-rich C-terminus as a ligand for Cu(II) ions. We studied the stoichiometry, stability, and spectroscopic features of copper complexes of the eight model peptides: L1Ac-DHDHHHGHAH, L2Ac-DKPAKAEDHDHHHGHAH, and six mutants of L2 in the pH range of 2–11. We revealed the impact of adjacent residues to the His-rich fragment on the complex stability: the presence of Lys and Asp residues significantly increases the stability of the system. The impact of His mutations was also examined: surprisingly, the exchange of each single His to the Gln residue did not disrupt the ability of the ligand to provide three binding sites for Cu(II) ions. Despite the most possible preference of the Cu(II) ion for the His9–His13 residues (Ac-DKPAKAEDHDHHH-) of the model peptide, especially the His11 residue, the study shows that there is not only one possible binding mode for Cu(II). The significance of this phenomenon is very important for the GroEL1 functionif the single mutation occurs naturally, the protein would be still able to interact with the metal ion.

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Section: Introductionmentioning

confidence: 99%

Histidine-Rich C-Terminal Tail of Mycobacterial GroEL1 and Its Copper Complex─The Impact of Point Mutations

et al. 2023

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“…GroEL1 contains a C-terminal histidine-rich region, which is a general feature of GroEL1 in actinobacteria. Recent studies showed that this region is involved in metal binding, which is required for GroEL1 function 66 , 67 , and it is possible that GroEL1 and PacL proteins evolved from a common ancestor to fulfill distinct functions.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial resistance to zinc poisoning requires assembly of P-ATPase-containing membrane metal efflux platforms

et al. 2022

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The human pathogen Mycobacterium tuberculosis requires a P1B-ATPase metal exporter, CtpC (Rv3270), for resistance to zinc poisoning. Here, we show that zinc resistance also depends on a chaperone-like protein, PacL1 (Rv3269). PacL1 contains a transmembrane domain, a cytoplasmic region with glutamine/alanine repeats and a C-terminal metal-binding motif (MBM). PacL1 binds Zn2+, but the MBM is required only at high zinc concentrations. PacL1 co-localizes with CtpC in dynamic foci in the mycobacterial plasma membrane, and the two proteins form high molecular weight complexes. Foci formation does not require flotillin nor the PacL1 MBM. However, deletion of the PacL1 Glu/Ala repeats leads to loss of CtpC and sensitivity to zinc. Genes pacL1 and ctpC appear to be in the same operon, and homologous gene pairs are found in the genomes of other bacteria. Furthermore, PacL1 colocalizes and functions redundantly with other PacL orthologs in M. tuberculosis. Overall, our results indicate that PacL proteins may act as scaffolds that assemble P-ATPase-containing metal efflux platforms mediating bacterial resistance to metal poisoning.

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“…GroEL1 contains a C-terminal histidine-rich region, which is a general feature of GroEL1 in actinobacteria. Recent studies showed that this region is involved in metal binding, which is required for GroEL1 function 65,66 , and it is possible that GroEL1 and PacL proteins evolved from a common ancestor to fulfil distinct functions.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial resistance to zinc poisoning requires assembly of P-ATPase-containing membrane metal efflux platforms

Boudehen

Faucher

Maréchal

et al. 2021

Preprint

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Transition metals are toxic at high concentrations. The P1B-ATPase metal exporter CtpC/Rv3270 is required for resistance to zinc poisoning in the human pathogen Mycobacterium tuberculosis. Here, we discovered that zinc resistance also depends on the chaperone-like protein PacL1/Rv3269. PacL1 bound Zn2+, but unlike PacL1 and CtpC, the PacL1 metal-binding motif (MBM) was required only at high zinc concentrations. PacL1 co-localized with CtpC in dynamic microdomains within the mycobacterial plasma membrane. Microdomain formation did not require flotillins nor the PacL1 MBM. Instead, loss of the PacL1 Glutamine/Alanine repeats led to loss of CtpC and sensitivity to zinc. PacL1 and CtpC are within the same operon, and homologous PacL1-P1B-ATPase pairs are widely distributed within and across prokaryotes. PacL1 colocalized and functioned redundantly with PacL orthologs in Mycobacterium tuberculosis. Overall, our study suggests that PacL proteins are scaffolds that assemble P-ATPase-containing metal efflux platforms, a novel type of functional membrane microdomain that underlies bacterial resistance to metal poisoning.

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A novel function of Mycobacterium tuberculosis chaperonin paralog GroEL1 in copper homeostasis

Cited by 12 publications

References 61 publications

Histidine-Rich C-Terminal Tail of Mycobacterial GroEL1 and Its Copper Complex─The Impact of Point Mutations

Histidine-Rich C-Terminal Tail of Mycobacterial GroEL1 and Its Copper Complex─The Impact of Point Mutations

Mycobacterial resistance to zinc poisoning requires assembly of P-ATPase-containing membrane metal efflux platforms

Mycobacterial resistance to zinc poisoning requires assembly of P-ATPase-containing membrane metal efflux platforms

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