Identification and characterization of a calmodulin binding domain in the plasma membrane Ca 2+ -ATPase from Trypanosoma equiperdum

Ramírez-Iglesias, José Rubén; Pérez-Gordones, María Carolina; Castillo, Jesús R. del; Mijares, Alfrédo; Benaím, Gustavo; Mendoza, M.

doi:10.1016/j.molbiopara.2018.04.005

Cited by 5 publications

(4 citation statements)

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“…In T. cruzi the PMCA also has been identified (Benaim et al, 1991), isolated by mean of a CaM-affinity column and partially characterized (Benaim et al, 1995), but appears to diverge from its human counterpart at the CaM-binding domain (Figure 2). Albeit the CaM-binding domain in T. cruzi PMCA (TcCa1) has not been characterized fully, recent studies on Trypanosoma equiperdum (a T. brucei-related hemoflagellate parasite that causes infection in cattle), have demonstrated that the CaM-binding domain of the PMCA of T. equiperdum possesses a non-canonical sequence (Perez-Gordones et al, 2017;Ramírez-Iglesias et al, 2018). This Ca 2+ -ATPase contains a 28 amino acid-region in the C-terminal tail that has been proposed to assume an α-helix conformation within a 1-18 (Trp-1, Phe-18) CaM binding motif (Perez-Gordones et al, 2017).…”

Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

“…This Ca 2+ -ATPase contains a 28 amino acid-region in the C-terminal tail that has been proposed to assume an α-helix conformation within a 1-18 (Trp-1, Phe-18) CaM binding motif (Perez-Gordones et al, 2017). Another difference is that unlike CaM in human cells, which interacts with the CaM-binding domain solely with the Cterminal half (78-148 aa) of the PMCA protein (Guerini et al, 1984), T. equiperdum CaM appears to wrap the CaM-binding domain of the parasite PMCA (Perez-Gordones et al, 2017;Ramírez-Iglesias et al, 2018). The sequence of the CaM-binding domain of T. equiperdum is very similar to that present in the in the T. cruzi PMCA, suggesting that with all likelihood, the characterization performed on the enzyme from T. equiperdum, can be extrapolated to the T. cruzi PMCA.…”

Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

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Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Benaím

Paniz‐Mondolfi

Sordillo

et al. 2020

Front. Cell. Infect. Microbiol.

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There is no effective cure for Chagas disease, which is caused by infection with the arthropod-borne parasite, Trypanosoma cruzi. In the search for new drugs to treat Chagas disease, potential therapeutic targets have been identified by exploiting the differences between the mechanisms involved in intracellular Ca 2+ homeostasis, both in humans and in trypanosomatids. In the trypanosomatid, intracellular Ca 2+ regulation requires the concerted action of three intracellular organelles, the endoplasmic reticulum, the single unique mitochondrion, and the acidocalcisomes. The single unique mitochondrion and the acidocalcisomes also play central roles in parasite bioenergetics. At the parasite plasma membrane, a Ca 2+-− ATPase (PMCA) with significant differences from its human counterpart is responsible for Ca 2+ extrusion; a distinctive sphingosine-activated Ca 2+ channel controls Ca 2+ entrance to the parasite interior. Several potential anti-trypansosomatid drugs have been demonstrated to modulate one or more of these mechanisms for Ca 2+ regulation. The antiarrhythmic agent amiodarone and its derivatives have been shown to exert trypanocidal effects through the disruption of parasite Ca 2+ homeostasis. Similarly, the amiodarone-derivative dronedarone disrupts Ca 2+ homeostasis in T. cruzi epimastigotes, collapsing the mitochondrial membrane potential (Ψ m), and inducing a large increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i) from this organelle and from the acidocalcisomes in the parasite cytoplasm. The same general mechanism has been demonstrated for SQ109, a new anti-tuberculosis drug with potent trypanocidal effect. Miltefosine similarly induces a large increase in the [Ca 2+ ] i acting on the sphingosine-activated Ca 2+ channel, the mitochondrion and acidocalcisomes. These examples, in conjunction with other evidence we review herein, strongly support targeting Ca 2+ homeostasis as a strategy against Chagas disease.

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Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Benaím

Paniz‐Mondolfi

Sordillo

et al. 2020

Front. Cell. Infect. Microbiol.

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“…At the plasma membrane it has been described a Ca 2+ ‐ATPase (PMCA) which extrudes this cation from the cytoplasm to the extracellular milieu with high affinity. This calmodulin‐dependent Ca 2+ pump has been identified in all trypanosomatids so far studied . Even though all the mentioned mechanisms in these parasites have been well documented and partially characterized, the mechanisms responsible for Ca 2+ entry into T. cruzi remain totally unknown.…”

Section: Introductionmentioning

confidence: 99%

Identification and electrophysiological properties of a sphingosine‐dependent plasma membrane Ca²⁺ channel in Trypanosoma cruzi

et al. 2019

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Trypanosoma cruzi is the causative agent of Chagas disease. The only two drugs accepted for the treatment of this infection are benznidazole and nifurtimox, which are of limited use in the predominant chronic phase. On the search for new drugs, the intracellular Ca2+ regulation has been postulated as a possible target, due to differences found between host cells and the parasite. The mechanisms involved in the intracellular Ca2+ regulation of T. cruzi have been partially elucidated. However, nothing is known about a putative channel responsible for the Ca2+ entry into this parasite. In contrast, in Leishmania spp., a closely related hemoflagelate, a sphingosine‐activated plasma membrane Ca2+ channel has been recently described. The latter resembles the L‐type voltage‐gated Ca2+ channel present in humans, but with distinct characteristics. This channel is one of the main targets concerning the mechanism of action of miltefosine, the unique oral drug approved against leishmaniasis. In the present work, we describe for the first time, the electrophysiological characterization of a sphingosine‐activated Ca2+ channel of T. cruzi by reconstituting plasma membrane vesicles into giant liposomes and patch clamp. This channel shares some characteristic as activation by Bay K8644 and inhibition by channel blockers such as nifedipine. However, the T. cruzi channel differs from the L‐type VGCC in its activation by sphingosine and/or miltefosine. Albeit the conductance for each, Ba2+, Ca2+ and Sr2+ was similar, the parasite channel appears not to be voltage dependent. A gene that presents homology in critical amino acids with its human ortholog Ca2+ channel was identified.

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“…Although some trypanosomatids apparently lack this C -terminal calmodulin binding domain, it has been shown that calmodulin stimulates the plasma membrane ATPase activity in T. brucei [ 40 ], T. cruzi [ 48 ] and L. mexicana [ 49 ]. In this regard, the presence of a CaM-binding domain was recently demonstrated in the C -terminal region of the PMCA of Trypanosoma equiperdum [ 50 , 51 ], a subspecies of T. brucei [ 52 ].…”

Section: Calcium Transport Proteins In the Plasma Membranementioning

confidence: 99%

Membrane Proteins in Trypanosomatids Involved in Ca2+ Homeostasis and Signaling

Ramakrishnan

Docampo

2018

Genes

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Calcium ion (Ca2+) serves as a second messenger for a variety of cell functions in trypanosomes. Several proteins in the plasma membrane, acidocalcisomes, endoplasmic reticulum, and mitochondria are involved in its homeostasis and in cell signaling roles. The plasma membrane has a Ca2+ channel for its uptake and a plasma membrane-type Ca2+-ATPase (PMCA) for its efflux. A similar PMCA is also located in acidocalcisomes, acidic organelles that are the primary Ca2+ store and that possess an inositol 1,4,5-trisphosphate receptor (IP3R) for Ca2+ efflux. Their mitochondria possess a mitochondrial calcium uniporter complex (MCUC) for Ca2+ uptake and a Ca2+/H+ exchanger for Ca2+ release. The endoplasmic reticulum has a sarcoplasmic-endoplasmic reticulum-type Ca2+-ATPase (SERCA) for Ca2+ uptake but no Ca2+ release mechanism has been identified. Additionally, the trypanosomatid genomes contain other membrane proteins that could potentially bind calcium and await further characterization.

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Identification and characterization of a calmodulin binding domain in the plasma membrane Ca 2+ -ATPase from Trypanosoma equiperdum

Cited by 5 publications

References 55 publications

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Identification and electrophysiological properties of a sphingosine‐dependent plasma membrane Ca²⁺ channel in Trypanosoma cruzi

Membrane Proteins in Trypanosomatids Involved in Ca2+ Homeostasis and Signaling

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Identification and characterization of a calmodulin binding domain in the plasma membrane Ca 2+ -ATPase from Trypanosoma equiperdum

Cited by 5 publications

References 55 publications

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Identification and electrophysiological properties of a sphingosine‐dependent plasma membrane Ca2+ channel in Trypanosoma cruzi

Membrane Proteins in Trypanosomatids Involved in Ca2+ Homeostasis and Signaling

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Identification and electrophysiological properties of a sphingosine‐dependent plasma membrane Ca²⁺ channel in Trypanosoma cruzi