scholarly journals A mysterious family of calcium-binding proteins from parasitic worms

2016 ◽  
Vol 44 (4) ◽  
pp. 1005-1010 ◽  
Author(s):  
Charlotte M. Thomas ◽  
David J. Timson
Keyword(s):  
Calcium Ions ◽  
Calcium Binding ◽  
Cell Biology ◽  
Fasciola Hepatica ◽  
Family Members ◽  
Ion Concentration ◽  
Pharmacological Significance ◽  
Ef Hand ◽  
Parasitic Worms

There is a family of proteins from parasitic worms which combine N-terminal EF-hand domains with C-terminal dynein light chain-like domains. Data are accumulating on the biochemistry and cell biology of these proteins. However, little is known about their functions in vivo. Schistosoma mansoni expresses 13 family members (SmTAL1–SmTAL13). Three of these (SmTAL1, SmTAL2 and SmTAL3) have been subjected to biochemical analysis which demonstrated that they have different molecular properties. Although their overall folds are predicted to be similar, small changes in the EF-hand domains result in differences in their ion binding properties. Whereas SmTAL1 and SmTAL2 are able to bind calcium (and some other) ions, SmTAL3 appears to be unable to bind any divalent cations. Similar biochemical diversity has been seen in the CaBP proteins from Fasciola hepatica. Four family members are known (FhCaBP1–4). All of these bind to calcium ions. However, FhCaBP4 dimerizes in the presence of calcium ions, FhCaBP3 dimerizes in the absence of calcium ions and FhCaBP2 dimerizes regardless of the prevailing calcium ion concentration. In both the SmTAL and FhCaBP families, the proteins also differ in their ability to bind calmodulin antagonists and related drugs. Interestingly, SmTAL1 interacts with praziquantel (the drug of choice for treating schistosomiasis). The pharmacological significance (if any) of this finding is unknown.

scholarly journals FhCaBP4: a Fasciola hepatica calcium-binding protein with EF-hand and dynein light chain domains

2012 ◽  
Vol 111 (4) ◽  
pp. 1707-1713 ◽  
Author(s):  
Rebecca Orr ◽  
Ruth Kinkead ◽  
Richard Newman ◽  
Lindsay Anderson ◽  
Elizabeth M. Hoey ◽  
...  
Keyword(s):  
Light Chain ◽  
Calcium Binding ◽  
Fasciola Hepatica ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Dynein Light Chain ◽  
Ef Hand

scholarly journals FhCaBP2: a Fasciola hepatica calcium-binding protein with EF-hand and dynein light chain domains

Parasitology ◽  
2015 ◽  
Vol 142 (11) ◽  
pp. 1375-1386 ◽  
Author(s):  
CHARLOTTE M. THOMAS ◽  
DAVID J. TIMSON
Keyword(s):  
Light Chain ◽  
Calcium Binding ◽  
Fasciola Hepatica ◽  
Biochemical Properties ◽  
Binding Activity ◽  
Ion Binding ◽  
Dynein Light Chain ◽  
Manganese Ions ◽  
Ef Hand ◽  
The One

SUMMARYFhCaBP2 is a Fasciola hepatica protein which belongs to a family of helminth calcium-binding proteins which combine an N-terminal domain containing two EF-hand motifs and a C-terminal dynein light chain-like (DLC-like) domain. Its predicted structure showed two globular domains joined by a flexible linker. Recombinant FhCaBP2 interacted reversibly with calcium and manganese ions, but not with magnesium, barium, strontium, copper (II), colbalt (II), iron (II), nickel, lead or potassium ions. Cadmium (II) ions appeared to bind non-site-specifically and destabilize the protein. Interaction with either calcium or magnesium ions results in a conformational change in which the protein's surface becomes more hydrophobic. The EF-hand domain alone was able to interact with calcium and manganese ions; the DLC-like domain was not. Alteration of a residue (Asp-58 to Ala) in the second EF-hand motif in this domain abolished ion-binding activity. This suggests that the second EF-hand is the one responsible for ion-binding. FhCaBP2 homodimerizes and the extent of dimerization was not affected by calcium ions or by the aspartate to alanine substitution in the second EF-hand. The isolated EF-hand and DLC-like domains are both capable of homodimerization. FhCaBP2 interacted with the calmodulin antagonists trifluoperazine, chlorpromazine, thiamylal and W7. Interestingly, while chlorpromazine and thiamylal interacted with the EF-hand domain (as expected), trifluoperazine and W7 bound to the DLC-like domain. Overall, FhCaBP2 has distinct biochemical properties compared with other members of this protein family from Fasciola hepatica, a fact which supports the hypothesis that these proteins have different physiological roles.

scholarly journals Calcium-dependent and -independent interactions of the S100 protein family

2006 ◽  
Vol 396 (2) ◽  
pp. 201-214 ◽  
Author(s):  
Liliana Santamaria-Kisiel ◽  
Anne C. Rintala-Dempsey ◽  
Gary S. Shaw
Keyword(s):  
Protein Interactions ◽  
Calcium Binding ◽  
S100 Protein ◽  
Cytoskeletal Proteins ◽  
S100 Proteins ◽  
Target Proteins ◽  
Calcium Dependent ◽  
Ef Hand

The S100 proteins comprise at least 25 members, forming the largest group of EF-hand signalling proteins in humans. Although the proteins are expressed in many tissues, each S100 protein has generally been shown to have a preference for expression in one particular tissue or cell type. Three-dimensional structures of several S100 family members have shown that the proteins assume a dimeric structure consisting of two EF-hand motifs per monomer. Calcium binding to these S100 proteins, with the exception of S100A10, results in an approx. 40° alteration in the position of helix III, exposing a broad hydrophobic surface that enables the S100 proteins to interact with a variety of target proteins. More than 90 potential target proteins have been documented for the S100 proteins, including the cytoskeletal proteins tubulin, glial fibrillary acidic protein and F-actin, which have been identified mostly from in vitro experiments. In the last 5 years, efforts have concentrated on quantifying the protein interactions of the S100 proteins, identifying in vivo protein partners and understanding the molecular specificity for target protein interactions. Furthermore, the S100 proteins are the only EF-hand proteins that are known to form both homo- and hetero-dimers, and efforts are underway to determine the stabilities of these complexes and structural rationales for their formation and potential differences in their biological roles. This review highlights both the calcium-dependent and -independent interactions of the S100 proteins, with a focus on the structures of the complexes, differences and similarities in the strengths of the interactions, and preferences for homo- compared with hetero-dimeric S100 protein assembly.

scholarly journals Friend or Foe: S100 Proteins in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2037 ◽  
Author(s):  
Chantal Allgöwer ◽  
Anna-Laura Kretz ◽  
Silvia von Karstedt ◽  
Mathias Wittau ◽  
Doris Henne-Bruns ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Current Knowledge ◽  
Neurological Diseases ◽  
Family Members ◽  
S100 Proteins ◽  
S100 Family ◽  
Cellular Processes ◽  
Ef Hand ◽  
Cancer Types ◽  
Novel Therapeutic Strategies

S100 proteins are widely expressed small molecular EF-hand calcium-binding proteins of vertebrates, which are involved in numerous cellular processes, such as Ca2+ homeostasis, proliferation, apoptosis, differentiation, and inflammation. Although the complex network of S100 signalling is by far not fully deciphered, several S100 family members could be linked to a variety of diseases, such as inflammatory disorders, neurological diseases, and also cancer. The research of the past decades revealed that S100 proteins play a crucial role in the development and progression of many cancer types, such as breast cancer, lung cancer, and melanoma. Hence, S100 family members have also been shown to be promising diagnostic markers and possible novel targets for therapy. However, the current knowledge of S100 proteins is limited and more attention to this unique group of proteins is needed. Therefore, this review article summarises S100 proteins and their relation in different cancer types, while also providing an overview of novel therapeutic strategies for targeting S100 proteins for cancer treatment.

scholarly journals X-ray, spectroscopic and normal-mode dynamics of calexcitin: structure–function studies of a neuronal calcium-signalling protein

2015 ◽  
Vol 71 (3) ◽  
pp. 615-631 ◽  
Author(s):  
P. T. Erskine ◽  
A. Fokas ◽  
C. Muriithi ◽  
H. Rehman ◽  
L. A. Yates ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Normal Mode ◽  
Calcium Ions ◽  
Calcium Binding ◽  
Calcium Binding Site ◽  
X Ray ◽  
Terminal Domain ◽  
Ef Hand ◽  
Ef Hands ◽  
Photoreceptor Neurons

The protein calexcitin was originally identified in molluscan photoreceptor neurons as a 20 kDa molecule which was up-regulated and phosphorylated following a Pavlovian conditioning protocol. Subsequent studies showed that calexcitin regulates the voltage-dependent potassium channel and the calcium-dependent potassium channel as well as causing the release of calcium ions from the endoplasmic reticulum (ER) by binding to the ryanodine receptor. A crystal structure of calexcitin from the squidLoligo pealeishowed that the fold is similar to that of another signalling protein, calmodulin, the N- and C-terminal domains of which are known to separate upon calcium binding, allowing interactions with the target protein. Phosphorylation of calexcitin causes it to translocate to the cell membrane, where its effects on membrane excitability are exerted and, accordingly,L. pealeicalexcitin contains two protein kinase C phosphorylation sites (Thr61 and Thr188). Thr-to-Asp mutations which mimic phosphorylation of the protein were introduced and crystal structures of the corresponding single and double mutants were determined, which suggest that the C-terminal phosphorylation site (Thr188) exerts the greatest effects on the protein structure. Extensive NMR studies were also conducted, which demonstrate that the wild-type protein predominantly adopts a more open conformation in solution than the crystallographic studies have indicated and, accordingly, normal-mode dynamic simulations suggest that it has considerably greater capacity for flexible motion than the X-ray studies had suggested. Like calmodulin, calexcitin consists of four EF-hand motifs, although only the first three EF-hands of calexcitin are involved in binding calcium ions; the C-terminal EF-hand lacks the appropriate amino acids. Hence, calexcitin possesses two functional EF-hands in close proximity in its N-terminal domain and one functional calcium site in its C-terminal domain. There is evidence that the protein has two markedly different affinities for calcium ions, the weaker of which is most likely to be associated with binding of calcium ions to the protein during neuronal excitation. In the current study, site-directed mutagenesis has been used to abolish each of the three calcium-binding sites of calexcitin, and these experiments suggest that it is the single calcium-binding site in the C-terminal domain of the protein which is likely to have a sensory role in the neuron.

scholarly journals FhCaBP3: A Fasciola hepatica calcium binding protein with EF-hand and dynein light chain domains

Biochimie ◽  
2013 ◽  
Vol 95 (4) ◽  
pp. 751-758 ◽  
Author(s):  
Samantha Banford ◽  
Orla Drysdale ◽  
Elizabeth M. Hoey ◽  
Alan Trudgett ◽  
David J. Timson
Keyword(s):  
Light Chain ◽  
Calcium Binding ◽  
Fasciola Hepatica ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Dynein Light Chain ◽  
Ef Hand

scholarly journals Comprehensive Analysis of the Prognosis of S100 Family Members and Their Relationship with Tumor-Infiltrating Immune Cells in Human Pancreatic Adenocarcinoma

2021 ◽  
Author(s):  
Yajun Ren ◽  
Bing Chen ◽  
Meng Zhang ◽  
Feng Xu
Keyword(s):  
Mrna Expression ◽  
Pancreatic Adenocarcinoma ◽  
Immune Cells ◽  
Calcium Binding ◽  
Expression Patterns ◽  
Family Members ◽  
Tumor Stage ◽  
Risk Models ◽  
S100 Family ◽  
Ef Hand

Abstract Background: S100 family members(S100s) are small molecular EF hand calcium binding proteins and widely expressed in many tissues and organs. S100s are shown to be biomarkers of disease progression and prognosis in various types of cancers. Nevertheless, the expression patterns, function, prognostic values of S100s and its association with tumor-infiltrating immune cells in Pancreatic Adenocarcinoma(PAAD) patients have not been systematically clarified. Methods: we explored that the expression and roles of the entire twenty S100s in PAAD patients by using the following public databases: Oncomine, GEPIA, cBioPortal, Metascape, STRING, TIMER and GeneMANIA.Results: The S100A2/A3/A4/A6/A8/A9/A10/A11/A13/A14/A16/B/P mRNA expression were significantly upregulated in PAAD patients. The mRNA expression of S100A3/A4/A5/A6/A10/A11/A14/A16/Z were significantly negatively related with the tumor stage in PAAD patients. We found that the S100A2/A3/A5/A10/A11/A14/A16 were significantly correlated with poor OS, whereas the increased levels of S100A1/B/G/Z were strongly associated with good OS. We found significant correlations among S100s and Tumor-Infiltrating Immune Cells. Cox proportional risk models revealed that B cells, Dendritic cells and S100A1/A5/A6/A8/A9/A13/A14 were significantly related with outcomes in PAAD patients. Conclusions: S100A2/A3/A10/A11/A14/A16 may serve as new diagnostic and prognostic biomarkers for PAAD patients and provide new clues for immunotherapy in PAAD patients.

The impact of confocal microscopy in biomedical research

1992 ◽  
Vol 50 (2) ◽  
pp. 1158-1159
Author(s):  
William B. Amos
Keyword(s):  
Cell Biology ◽  
Three Dimensional ◽  
Optical Microscope ◽  
Ion Concentration ◽  
Reaction Products ◽  
Embryonic Life ◽  
The Many ◽  
Calcium Ion Concentration ◽  
The Impact

The confocal optical microscope, using laser illumination, has now gained widespread acceptance (see volume edited by Pawley) Its advantage in providing clear optical sections, particularly with fluorescent specimens, is well known. Of the many confocal instruments now in use in cell biology, the applications can be classified into five different categories.The chief use is to give three-dimensional information about conventionally prepared fluorescent specimens. A notable example is the in vivo mapping of an identified neurone through several days of embryonic life by O'Rourke, Scott Fraser and colleagues at Irvine, USA. There has also been much work on in situ hybridisation, morphometry of solid tumours, oncogene product localisation and many aspects of the cytoskeleton.The second use has been in reflection imaging of cell surface contacts, of isolated microtubules and microorganisms, of parts of the eye and of reaction products such as peroxidase.The third application is the measurement of intracellular parameters such as pH and calcium ion concentration within a defined volume.

Solution structure of TbCentrin4 from Trypanosoma brucei and its interactions with Ca2+ and other centrins

2018 ◽  
Vol 475 (23) ◽  
pp. 3763-3778 ◽  
Author(s):  
Fangzhen Shan ◽  
Kaiqin Ye ◽  
Jiahai Zhang ◽  
Shanhui Liao ◽  
Xuecheng Zhang ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Calcium Binding ◽  
Solution Structure ◽  
Structural Basis ◽  
Titration Calorimetry ◽  
Resonance Spectroscopy ◽  
Basal Bodies ◽  
High Concentration ◽  
Ef Hand

Centrin is a conserved calcium-binding protein that plays an important role in diverse cellular biological processes such as ciliogenesis, gene expression, DNA repair and signal transduction. In Trypanosoma brucei, TbCentrin4 is mainly localized in basal bodies and bi-lobe structure, and is involved in the processes coordinating karyokinesis and cytokinesis. In the present study, we solved the solution structure of TbCentrin4 using NMR (nuclear magnetic resonance) spectroscopy. TbCentrin4 contains four EF-hand motifs consisting of eight α-helices. Isothermal titration calorimetry experiment showed that TbCentrin4 has a strong Ca2+ binding ability. NMR chemical shift perturbation indicated that TbCentrin4 binds to Ca2+ through its C-terminal domain composed of EF-hand 3 and 4. Meanwhile, we revealed that TbCentrin4 undergoes a conformational change and self-assembly induced by high concentration of Ca2+. Intriguingly, localization of TbCentrin4 was dispersed or disappeared from basal bodies and the bi-lobe structure when the cells were treated with Ca2+in vivo, implying the influence of Ca2+ on the cellular functions of TbCentrin4. Besides, we observed the interactions between TbCentrin4 and other Tbcentrins and revealed that the interactions are Ca2+ dependent. Our findings provide a structural basis for better understanding the biological functions of TbCentrin4 in the relevant cellular processes.

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