Structural Biology of Copper Trafficking

Boal, Amie K.; Rosenzweig, Amy C.

doi:10.1021/cr900104z

Cited by 364 publications

(394 citation statements)

References 180 publications

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“…The preference of Cu(I) for soft bases (His, Cys, and Met) is manifest in the coordination environments of cytoplasmic metallochaperones (35)(36)(37) and the Met-rich sites found in periplasmic copperbinding proteins (38)(39)(40)(41). However, in the context of Cu(I) transport through membrane channels, kinetic lability may be more important than thermodynamic stability, and indeed high binding affinity is likely to inhibit transport, unless accompanied by energy input that can toggle high-and low-affinity states via conformational change, as has been proposed as a mechanism for intramembrane transport in P1B-type ATPases (42).…”

Section: Cusf and Cusb May Exchange Metal As Part Of A Regulatory Strmentioning

confidence: 99%

Tracking metal ions through a Cu/Ag efflux pump assigns the functional roles of the periplasmic proteins

Chacón

Mealman

McEvoy

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Copper is an essential nutrient for all aerobic organisms but is toxic in excess. At the host-pathogen interface, macrophages respond to bacterial infection by copper-dependent killing mechanisms, whereas the invading bacteria are thought to counter with an up-regulation of copper transporters and efflux pumps. The tripartite efflux pump CusCBA and its metallochaperone CusF are vital to the detoxification of copper and silver ions in the periplasm of Escherichia coli. However, the mechanism of efflux by this complex, which requires the activation of the inner membrane pump CusA, is poorly understood. Here, we use selenomethionine (SeM) active site labels in a series of biological X-ray absorption studies at the selenium, copper, and silver edges to establish a "switch" role for the membrane fusion protein CusB. We determine that metal-bound CusB is required for activation of cuprous ion transfer from CusF directly to a site in the CusA antiporter, showing for the first time (to our knowledge) the in vitro activation of the Cus efflux pump. This metal-binding site of CusA is unlike that observed in the crystal structures of the CusA protein and is composed of one oxygen and two sulfur ligands. Our results suggest that metal transfer occurs between CusF and apo-CusB, and that, when metal-loaded, CusB plays a role in the regulation of metal ion transfer from CusF to CusA in the periplasm.copper | periplasmic efflux | X-ray absorption spectroscopy | metal ion transport | host-pathogen interaction

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Section: Cusf and Cusb May Exchange Metal As Part Of A Regulatory Strmentioning

confidence: 99%

Tracking metal ions through a Cu/Ag efflux pump assigns the functional roles of the periplasmic proteins

Chacón

Mealman

McEvoy

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…1 Both authors contributed equally to this work. 2 To whom correspondence should be addressed. E-mail: rbanerje@umich.…”

Section: B 12 Chemistry and Catalysismentioning

confidence: 99%

“…Similarly, elaboration of metals into clusters often occurs on chaperones that subsequently transfer the cofactor to target proteins. The interprotein transfer of metals can occur via ligand exchange reactions that are driven by differences in metal coordination geometry and affinity between the donor and acceptor proteins (2,3). Seclusion of cofactors in chaperones during assembly/processing into their active forms minimizes unwanted side reactions, whereas guided delivery averts dilution and promotes specificity of cofactor docking.…”

mentioning

confidence: 99%

Navigating the B12 Road: Assimilation, Delivery, and Disorders of Cobalamin

Gherasim

Lofgren

Banerjee

2013

Journal of Biological Chemistry

168

120

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The reactivity of the cobalt-carbon bond in cobalamins is the key to their chemical versatility, supporting both methyl transfer and isomerization reactions. During evolution of higher eukaryotes that utilize vitamin B 12 , the high reactivity of the cofactor coupled with its low abundance pressured development of an efficient system for uptake, assimilation, and delivery of the cofactor to client B 12 -dependent enzymes. Although most proteins suspected to be involved in B 12 trafficking were discovered by 2009, the recent identification of a new protein reveals that the quest for elucidating the intracellular B 12 highway is still far from complete. Herein, we review the biochemistry of cobalamin trafficking.Cofactors are variously deployed in nature to stabilize macromolecular structures, expand catalytic functionality, transport gases, transduce signals, and function as sensors. Due to their relative rarity and/or reactivity, cells have evolved strategies for sequestering and regulating the movement of cofactors from their point of entry into the cell to their point of docking in target proteins (1). A subset of cofactors, i.e. the vitamins, is obtained in a precursor form from the diet. Reactions catalyzing the assimilation of inactive cofactors into their active forms are integral to their trafficking pathways. Similarly, elaboration of metals into clusters often occurs on chaperones that subsequently transfer the cofactor to target proteins. The interprotein transfer of metals can occur via ligand exchange reactions that are driven by differences in metal coordination geometry and affinity between the donor and acceptor proteins (2, 3). Seclusion of cofactors in chaperones during assembly/processing into their active forms minimizes unwanted side reactions, whereas guided delivery averts dilution and promotes specificity of cofactor docking.In contrast to our understanding of cellular strategies used for trafficking metals (4 -6) and metal clusters (7), significantly less is known about strategies for shepherding organic and organometallic cofactors to target proteins. This picture has been changing, however, with the convergence of clinical genetics and biochemical approaches that are beginning to illuminate an elaborate pathway for assimilation and delivery of dietary vitamin B 12 or cobalt-containing cobalamin, a complex organometallic cofactor (8 -10). Much less is known about how the tetrapyrrolic cousins of B 12 , e.g. iron protoporphyrin (heme), nickel corphin (F430), and magnesium chlorin (chlorophyll), are guided to specific destinations.In this minireview, we describe a model for mammalian cobalamin trafficking, which includes strategies for conversion of inactive precursors to the active cofactor forms methylcobalamin (MeCbl) 3 and 5Ј-deoxyadenosylcobalamin (AdoCbl; coenzyme B 12 ) and discuss the human diseases that result from impairments along the trafficking highway. We posit that the navigation strategy for B 12 , in which a rare, reactive, and high value cofactor is sequestered and targ...

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“…Good recent reviews of biological copper (Boal and Rosenzweig 2009;Banci, Bertini et al 2010;Lutsenko 2010), iron (Kosman 2010), and zinc (Eide 2006;Tomat and Lippard 2010) exist. Our understanding of the location and bioavailability of metals, until rather recently, was mainly accessible by studying the properties of the proteins that bind them.…”

Section: The Location Of Metals and Bioavailability Within The Cellmentioning

confidence: 99%

Inorganic Signatures of Physiology: The X-Ray Fluorescence Microscopy Revolution

Finney¹

2012

Biomarker

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Structural Biology of Copper Trafficking

Cited by 364 publications

References 180 publications

Tracking metal ions through a Cu/Ag efflux pump assigns the functional roles of the periplasmic proteins

Tracking metal ions through a Cu/Ag efflux pump assigns the functional roles of the periplasmic proteins

Navigating the B12 Road: Assimilation, Delivery, and Disorders of Cobalamin

Inorganic Signatures of Physiology: The X-Ray Fluorescence Microscopy Revolution

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