The structural basis of bacterial manganese import

Neville, Stephanie L.; Sjöhamn, Jennie; Watts, Jacinta A.; MacDermott-Opeskin, Hugo; Fairweather, Stephen J.; Ganio, Katherine; Hulyer, Alex Carey; McGrath, Aaron P.; Hayes, Andrew; Malcolm, Tess R.; Davies, Mark R.; Nomura, Norimichi; Iwata, So; O’Mara, Megan L.; Maher, M.J.; McDevitt, Christopher A.

doi:10.1126/sciadv.abg3980

Cited by 25 publications

(23 citation statements)

References 83 publications

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“…The ABC family of transporters are the primary streptococcal Mn importers and the best studied. All the characterized ABC-family Mn importers share similar molecular architecture and are composed of three components: a surface-exposed, membrane anchored solute binding protein that binds to extracellular Mn with high affinity, an integral membrane protein that mediates Mn influx, and a cytoplasmic ATPase that facilitates Mn import by ATP hydrolysis ( Li et al, 2014 ; Neville et al, 2021 ). The well characterized ABC transporters that are involved in streptococcal Mn acquisition include PsaBCA of S. pneumoniae , MtsABC of S. pyogenes , ScaCBA of S. gordonii , SloABC of S. mutans , TroABC of S. suis , SsaACB of S. sanguinis , and FimABC of S. parasanguinis ( Burnette-Curley et al, 1995 ; Berry & Paton, 1996 ; Kolenbrander et al, 1998 ; Kitten et al, 2000 ; Janulczyk et al, 2003 ; Paik et al, 2003 ; Johnston et al, 2004 ; Schreur et al, 2011 ; Crump et al, 2014 ; Kajfasz et al, 2020 ) .…”

Section: Streptococcal Strategies To Acquire Manganesementioning

confidence: 99%

Managing Manganese: The Role of Manganese Homeostasis in Streptococcal Pathogenesis

Aggarwal

Kumaraswami

2022

Front. Cell Dev. Biol.

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Pathogenic streptococci require manganese for survival in the host. In response to invading pathogens, the host recruits nutritional immune effectors at infection sites to withhold manganese from the pathogens and control bacterial growth. The manganese scarcity impairs several streptococcal processes including oxidative stress defenses, de novo DNA synthesis, bacterial survival, and virulence. Emerging evidence suggests that pathogens also encounter manganese toxicity during infection and manganese excess impacts streptococcal virulence by manganese mismetallation of non-cognate molecular targets involved in bacterial antioxidant defenses and cell division. To counter host-imposed manganese stress, the streptococcal species employ a sophisticated sensory system that tightly coordinates manganese stress-specific molecular strategies to negate host induced manganese stress and proliferate in the host. Here we review the molecular details of host-streptococcal interactions in the battle for manganese during infection and the significance of streptococcal effectors involved to bacterial pathophysiology.

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Section: Streptococcal Strategies To Acquire Manganesementioning

confidence: 99%

Managing Manganese: The Role of Manganese Homeostasis in Streptococcal Pathogenesis

Aggarwal

Kumaraswami

2022

Front. Cell Dev. Biol.

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“…It suggests there is likely a mechanism that cells have evolved to ensure active Mn(II) acquisition by Mn(II) specific ABC importers. (52, 53). Heddle et al .…”

Section: Resultsmentioning

confidence: 99%

“…It suggests there is likely a mechanism that cells have evolved to ensure active Mn(II) acquisition by Mn(II) specific ABC importers. (52,53). have hinted at this by calculating there to be ~120 μM of an NiBP (e.g., EcNikA) in the periplasmic space of an E. coli cell.…”

Section: Metal Promiscuity Screening By Automated Assaysmentioning

confidence: 99%

Ni(II) binding affinity and specificity of solute binding proteins: the importance of the double His motif and variable loop revealed by structural and mutational studies

Diep

Stogios

Evdokimova

et al. 2022

Preprint

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Extracytoplasmic solute binding proteins (SBPs) are molecular shuttles involved in the cellular uptake of various small molecules and metal ions including Ni(II). Our previous study with the Ni(II) binding proteins (NiBPs) CjNikZ from Campylobacter jejuni and CcNikZ-II from Clostridium carboxidivorans demonstrated that they were able to bind Ni(II) at low micromolar affinity without the need for additional chelators. Here, we determined the crystal structure of apo-CcNikZ-II, which revealed a Ni(II) binding site comprised of the double His (HH-)prong (His511, His512) and a short variable (v-)loop nearby (Thr59-Thr64, TEDKYT). Alanine scanning mutagenesis of the CcNikZ-II Ni(II) binding site identified Glu60 and His511 as critical for high affinity Ni(II) binding. Phylogenetic analysis of SBP sequences demonstrated the presence of 13 protein clusters with two groups containing the HH-prong. Metal binding assays with nine purified SBPs containing the HH-prong and v-loop revealed high Ni(II) binding affinity without requirement for chelators indicating that the double His prong represents a signature motif for the presence of chelate-free Ni(II) binding activity in SBPs. The engineered CcNikZ-II variants with the wild type v-loop (TEDKYT) replaced with v-loops from NiBPs with higher affinity showed up to an order of magnitude higher affinity for Ni(II). In addition, the v-loop appears to play a role in metal ion specificity as purified wild type and engineered NiBPs with different v-loop sequences showed distinct metal profiles. This work paves way for metalloprotein engineering of NiBPs towards biocatalytic and metal recovery applications.

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“…For example, extracellular Zn competitively inhibits Mn uptake via PsaABC in S. pneumoniae 8,9 . The permeases PsaB (which imports Mn) and AdcB (which imports Zn) in this organism possess the same, conserved metal coordination site 46 , suggesting that PsaB should be competent to receive Zn from PsaA. However, while PsaC efficiently releases the bound Mn to PsaB, it does not release bound Zn 45 .…”

Section: Do Abc Transporters Promote Cu Uptake Into Gas?mentioning

confidence: 95%

Mis-regulation of Zn and Mn homeostasis is a key phenotype of Cu stress inStreptococcus pyogenes

Hong¹,

Mackenzie²,

Firth³

et al. 2022

Preprint

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All bacteria possess homeostastic mechanisms that control the availability of micronutrient metals within the cell. Regulatory cross-talks between different metal homeostasis pathways within the same bacterial organism have been reported widely. In addition, there have been previous suggestions that some metal uptake transporters can promote adventitious uptake of the wrong metal. This work describes the cross-talk between the Cu homeostasis pathway and the Zn, Mn, and Fe pathways in Group A Streptococcus (GAS). Using a ∆copA mutant strain that lacks the primary Cu efflux pump and thus traps excess Cu in the cytoplasm, we show that Cu stress leads to strong downregulation of Zn and Mn uptake genes, and mild downregulation of Fe uptake genes. This effect is associated with depletion of cellular Zn levels, but not those of Mn or Fe. Co-supplementation of the culture medium with Zn and, to a lesser extent, Mn, but not Fe alleviates key Cu stress phenotypes, namely bacterial growth and production of the fermentation end-product lactate. However, neither Zn nor Mn treatment influences cellular Cu levels or Cu availability in Cu-stressed cells. In addition, we show that the Zn and Mn uptake transporters in GAS do not promote Cu uptake. Taken together, the results strengthen and extend our previous proposal that mis-repression of Zn uptake genes and cellular Zn depletion are key mechanisms of Cu stress in GAS. By comparison, although Mn homeostasis in GAS is perturbed during Cu stress, the relationship between the two metals is yet to be defined.

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The structural basis of bacterial manganese import

Cited by 25 publications

References 83 publications

Managing Manganese: The Role of Manganese Homeostasis in Streptococcal Pathogenesis

Managing Manganese: The Role of Manganese Homeostasis in Streptococcal Pathogenesis

Ni(II) binding affinity and specificity of solute binding proteins: the importance of the double His motif and variable loop revealed by structural and mutational studies

Mis-regulation of Zn and Mn homeostasis is a key phenotype of Cu stress inStreptococcus pyogenes

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