scholarly journals Allosteric activation of yeast enzyme neutral trehalase by calcium and 14-3-3 protein

2019 ◽  
pp. 147-160 ◽  
Author(s):  
M. Alblova ◽  
A. Smidova ◽  
D. Kalabova ◽  
D. Lentini Santo ◽  
T. Obsil ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Activation Mechanism ◽  
Structural Basis ◽  
Adverse Conditions ◽  
Cellular Processes ◽  
Neutral Trehalase ◽  
Allosteric Effectors ◽  
Ef Hand ◽  
Eukaryotic Organism ◽  
Partner Proteins

Neutral trehalase 1 (Nth1) from Saccharomyces cerevisiae catalyzes disaccharide trehalose hydrolysis and helps yeast to survive adverse conditions, such as heat shock, starvation or oxidative stress. 14-3-3 proteins, master regulators of hundreds of partner proteins, participate in many key cellular processes. Nth1 is activated by phosphorylation followed by 14-3-3 protein (Bmh) binding. The activation mechanism is also potentiated by Ca(2+) binding within the EF-hand-like motif. This review summarizes the current knowledge about trehalases and the molecular and structural basis of Nth1 activation. The crystal structure of fully active Nth1 bound to 14-3-3 protein provided the first high-resolution view of a trehalase from a eukaryotic organism and showed 14-3-3 proteins as structural modulators and allosteric effectors of multi-domain binding partners.

scholarly journals Proposed model of the Dictyostelium cAMP receptors bound to cAMP

2019 ◽  
Author(s):  
Jack Calum Greenhalgh ◽  
Aneesh Chandran ◽  
Matthew Thomas Harper ◽  
Graham Ladds ◽  
Taufiq Rahman
Keyword(s):  
Homology Modelling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Structural Features ◽  
Activation Mechanism ◽  
Ligand Docking ◽  
Structural Basis ◽  
Intracellular Camp ◽  
Cellular Processes ◽  
Developmental Signalling

Abstract3’,5’-cyclic adenosine monophosphate (cAMP) is well known as a ubiquitous intracellular messenger regulating a diverse array of cellular processes. However, for a group of social amoebae or Dictyostelia undergoing starvation, intracellular cAMP is secreted in a pulsatile manner to their exterior. This then uniquely acts as a first messenger, triggering aggregation of the starving amoebae followed by their developmental progression towards multicellular fruiting bodies formation. Such developmental signalling for extracellularly-acting cAMP is well studied in the popular dictyostelid,Dictyostelium discoideum, and is mediated by a distinct family (‘class E’) of G protein-coupled receptors (GPCRs) collectively designated as the cAMP receptors (cARs). Whilst the biochemical aspects of these receptors are well characterised, little is known about their overall 3D architecture and structural basis for cAMP recognition and subtype-dependent changes in binding affinity. Using a ligand docking-guided homology modelling approach, we hereby present for the first time, plausible models of active forms of the cARs fromD. discoideum. Our models highlight some structural features that may underlie the differential affinities of cAR isoforms for cAMP binding and also suggest few residues that may play important roles for the activation mechanism of this GPCR family.

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.

FYVE-finger proteins--effectors of an inositol lipid

1999 ◽  
Vol 112 (23) ◽  
pp. 4175-4183 ◽  
Author(s):  
H. Stenmark ◽  
R. Aasland
Keyword(s):  
Membrane Trafficking ◽  
Current Knowledge ◽  
Structural Basis ◽  
Membrane Recruitment ◽  
Cellular Processes ◽  
Receptor Signalling ◽  
Cytoskeletal Function ◽  
Phosphoinositide 3 Kinase ◽  
Derivatives Of ◽  
Review Current

The binding of cytosolic proteins to specific intracellular membranes containing phosphorylated derivatives of phosphatidylinositol (PtdIns) is a common theme in vital cellular processes, such as cytoskeletal function, receptor signalling and membrane trafficking. Recently, several potential effectors of the phosphoinositide 3-kinase product PtdIns 3-phosphate (PtdIns(3)P) have emerged through the observation that a conserved zinc-finger-like domain, the FYVE-finger, binds specifically to this lipid. Here we review current knowledge about the structural basis for the FYVE-PtdIns(3)P interaction, its role in membrane recruitment of proteins and the functions of FYVE-finger proteins in membrane trafficking and other cellular processes.

scholarly journals Structural Basis for the Functional Diversity of Centrins: A Focus on Calcium Sensing Properties and Target Recognition

2021 ◽  
Vol 22 (22) ◽  
pp. 12173
Author(s):  
Marco Pedretti ◽  
Luca Bombardi ◽  
Carolina Conter ◽  
Filippo Favretto ◽  
Paola Dominici ◽  
...  
Keyword(s):  
Size Structure ◽  
Current Knowledge ◽  
Structural Basis ◽  
Cellular Functions ◽  
Sensing Properties ◽  
Calcium Sensing ◽  
Depth Analysis ◽  
Ef Hand ◽  
Insight Into ◽  
Functional Versatility

Centrins are a family of small, EF hand-containing proteins that are found in all eukaryotes and are often complexed with centrosome-related structures. Since their discovery, centrins have attracted increasing interest due to their multiple, diverse cellular functions. Centrins are similar to calmodulin (CaM) in size, structure and domain organization, although in contrast to CaM, the majority of centrins possess at least one calcium (Ca2+) binding site that is non-functional, thus displaying large variance in Ca2+ sensing abilities that could support their functional versatility. In this review, we summarize current knowledge on centrins from both biophysical and structural perspectives with an emphasis on centrin-target interactions. In-depth analysis of the Ca2+ sensing properties of centrins and structures of centrins complexed with target proteins can provide useful insight into the mechanisms of the different functions of centrins and how these proteins contribute to the complexity of the Ca2+ signaling cascade. Moreover, it can help to better understand the functional redundancy of centrin isoforms and centrin-binding proteins.

scholarly journals Computational Design of Macrocyclic Binders of S100B(ββ): Novel Peptide Theranostics

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 721
Author(s):  
Srinivasaraghavan Kannan ◽  
Pietro G. A. Aronica ◽  
Thanh Binh Nguyen ◽  
Jianguo Li ◽  
Chandra S. Verma
Keyword(s):  
Molecular Dynamics ◽  
Computational Design ◽  
Diagnostic Tools ◽  
Stapled Peptides ◽  
Altered Expression ◽  
Cellular Processes ◽  
High Affinity ◽  
Limited Success ◽  
Dynamics Simulations ◽  
Partner Proteins

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.

scholarly journals Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shirley Tremel ◽  
Yohei Ohashi ◽  
Dustin R. Morado ◽  
Jessie Bertram ◽  
Olga Perisic ◽  
...  
Keyword(s):  
Complex I ◽  
Kinase Domain ◽  
Beclin 1 ◽  
Structural Basis ◽  
Rab Gtpases ◽  
Lipid Kinase ◽  
Complex Ii ◽  
Cellular Processes ◽  
Specific Complex ◽  
Electron Cryotomography

AbstractThe lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a–GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations.

scholarly journals The Chinese Medicinal Formulation Guzhi Zengsheng Zhitongwan Modulates Chondrocyte Structure, Dynamics, and Metabolism by Controlling Multiple Functional Proteins

2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Baojin Yao ◽  
Bocheng Lu ◽  
Mei Zhang ◽  
Hongwei Gao ◽  
Xiangyang Leng ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Research Field ◽  
Medical Systems ◽  
Cellular Processes ◽  
Structure Dynamics ◽  
National Medical ◽  
Medicinal Formulation

Traditional Chinese medicine is one of the oldest medical systems in the world and has its unique principles and theories in the prevention and treatment of human diseases, which are achieved through the interactions of different types of materia medica in the form of Chinese medicinal formulations. GZZSZTW, a classical and effective Chinese medicinal formulation, was designed and created by professor Bailing Liu who is the only national medical master professor in the clinical research field of traditional Chinese medicine and skeletal diseases. GZZSZTW has been widely used in clinical settings for several decades for the treatment of joint diseases. However, the underlying molecular mechanisms are still largely unknown. In the present study, we performed quantitative proteomic analysis to investigate the effects of GZZSZTW on mouse primary chondrocytes using state-of-the-art iTRAQ technology. We demonstrated that the Chinese medicinal formulation GZZSZTW modulates chondrocyte structure, dynamics, and metabolism by controlling multiple functional proteins that are involved in the cellular processes of DNA replication and transcription, protein synthesis and degradation, cytoskeleton dynamics, and signal transduction. Thus, this study has expanded the current knowledge of the molecular mechanism of GZZSZTW treatment on chondrocytes. It has also shed new light on possible strategies to further prevent and treat cartilage-related diseases using traditional Chinese medicinal formulations.

The role of hypoxia in endometrial cancer

2021 ◽  
Vol 22 ◽  
Author(s):  
Yarely M. Salinas-Vera ◽  
Dolores Gallardo-Rincón ◽  
Erika Ruíz-García ◽  
Macrina B. Silva-Cázares ◽  
Carmen Sol de la Peña-Cruz ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Targeted Therapies ◽  
Current Knowledge ◽  
Vasculogenic Mimicry ◽  
Cellular Processes ◽  
Corpus Uteri

: Endometrial cancer represents the most frequent neoplasia from the corpus uteri, and comprises the 14th leading cause of death in women worldwide. Risk factors that contribute to the disease include early menarche, late menopause, nulliparity, and menopausal hormone use, as well as hypertension and obesity comorbidities. The clinical effectiveness of chemotherapy is variable, suggesting that novel molecular targeted therapies against specific cellular processes associated with the maintenance of cancer cell survival and therapy resistance urged to ameliorate the rates of success in endometrial cancer treatment. In the course of tumor growth, cancer cells must adapt to decreased oxygen availability in the microenvironment by upregulation of hypoxia-inducible factors, which orchestrate the activation of a transcriptional program leading to cell survival. During this adaptative process, the hypoxic cancer cells may acquire invasive and metastatic properties as well as increased cell proliferation and resistance to chemotherapy, enhanced angiogenesis, vasculogenic mimicry, and maintenance of cancer cell stemness, which contribute to more aggressive cancer phenotypes. Several studies have shown that hypoxia-inducible factor 1 alpha (HIF-1α) protein is aberrantly overexpressed in many solid tumors from breast, prostate, ovarian, bladder, colon, brain, and pancreas. Thus, it has been considered an important therapeutic target. Here, we reviewed the current knowledge of the relevant roles of cellular hypoxia mechanisms and HIF-1α functions in diverse processes associated with endometrial cancer progression. In addition, we also summarize the role of microRNAs in the posttranscriptional regulation of protein-encoding genes involved in the hypoxia response in endometrial cancer. Finally, we pointed out the need for urgent targeted therapies to impair the cellular processes activated by hypoxia in the tumor microenvironment.

Mechanisms of Giardia lamblia differentiation into cysts

1997 ◽  
Vol 61 (3) ◽  
pp. 294-304
Author(s):  
H D Luján ◽  
M R Mowatt ◽  
T E Nash
Keyword(s):  
Giardia Lamblia ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Life Cycles ◽  
Eukaryotic Cells ◽  
Organelle Biogenesis ◽  
Adaptive Responses ◽  
Specific Stimulus ◽  
Adverse Conditions

Microbiologists have long been intrigued by the ability of parasitic organisms to adapt to changes in the environment. Since most parasites occupy several niches during their journey between vectors and hosts, they have developed adaptive responses which allow them to survive under adverse conditions. Therefore, the life cycles of protozoan and helminthic parasites are excellent models with which to study numerous mechanisms involved in cell differentiation, such as the regulation of gene expression, signal transduction pathways, and organelle biogenesis. Unfortunately, many of these studies are very difficult because the conditions needed to elicit developmental changes in parasites remain undetermined in most cases. Recently, several interesting findings were reported on the process of differentiation of Giardia lamblia trophozoites into cysts. G. lamblia is a flagellated protozoan that inhabits the upper small intestine of its vertebrate host and is a major cause of enteric disease worldwide. It belongs to the earliest identified lineage among eukaryotes and therefore offers a unique insight into the progression from primitive to more complex eukaryotic cells. The discovery of a specific stimulus that induces trophozoites to differentiate into cysts, the identification and characterization of encystation-specific molecules, the elucidation of novel biochemical pathways, and the development of useful reagents and techniques have made this parasite an excellent model with which to study differentiation in eukaryotic cells. In this review, we summarize the most recent fundings on several aspects of Giardia differentiation and discuss the significance of these findings within the context of current knowledge in the field.

scholarly journals Hanks-Type Serine/Threonine Protein Kinases and Phosphatases in Bacteria: Roles in Signaling and Adaptation to Various Environments

2018 ◽  
Vol 19 (10) ◽  
pp. 2872 ◽  
Author(s):  
Monika Janczarek ◽  
José-María Vinardell ◽  
Paulina Lipa ◽  
Magdalena Karaś
Keyword(s):  
Dna Binding ◽  
Essential Role ◽  
Current Knowledge ◽  
Response Regulator ◽  
Protein Targets ◽  
Regulatory Pathways ◽  
Translational Machinery ◽  
Signaling Systems ◽  
Cellular Processes ◽  
Division Cell

Reversible phosphorylation is a key mechanism that regulates many cellular processes in prokaryotes and eukaryotes. In prokaryotes, signal transduction includes two-component signaling systems, which involve a membrane sensor histidine kinase and a cognate DNA-binding response regulator. Several recent studies indicate that alternative regulatory pathways controlled by Hanks-type serine/threonine kinases (STKs) and serine/threonine phosphatases (STPs) also play an essential role in regulation of many different processes in bacteria, such as growth and cell division, cell wall biosynthesis, sporulation, biofilm formation, stress response, metabolic and developmental processes, as well as interactions (either pathogenic or symbiotic) with higher host organisms. Since these enzymes are not DNA-binding proteins, they exert the regulatory role via post-translational modifications of their protein targets. In this review, we summarize the current knowledge of STKs and STPs, and discuss how these enzymes mediate gene expression in prokaryotes. Many studies indicate that regulatory systems based on Hanks-type STKs and STPs play an essential role in the regulation of various cellular processes, by reversibly phosphorylating many protein targets, among them several regulatory proteins of other signaling cascades. These data show high complexity of bacterial regulatory network, in which the crosstalk between STK/STP signaling enzymes, components of TCSs, and the translational machinery occurs. In this regulation, the STK/STP systems have been proved to play important roles.

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