scholarly journals STRIPAK, a highly conserved signaling complex, controls multiple eukaryotic cellular and developmental processes and is linked with human diseases

2019 ◽  
Vol 400 (8) ◽  
pp. 1005-1022 ◽  
Author(s):  
Ulrich Kück ◽  
Daria Radchenko ◽  
Ines Teichert
Keyword(s):  
Protein Complexes ◽  
Model Systems ◽  
Human Diseases ◽  
Physical Interaction ◽  
Developmental Processes ◽  
Signaling Complex ◽  
Macromolecular Assembly ◽  
Complex Functions ◽  
Key Issues ◽  
Eukaryotic Organisms

Abstract The striatin-interacting phosphatases and kinases (STRIPAK) complex is evolutionary highly conserved and has been structurally and functionally described in diverse lower and higher eukaryotes. In recent years, this complex has been biochemically characterized better and further analyses in different model systems have shown that it is also involved in numerous cellular and developmental processes in eukaryotic organisms. Further recent results have shown that the STRIPAK complex functions as a macromolecular assembly communicating through physical interaction with other conserved signaling protein complexes to constitute larger dynamic protein networks. Here, we will provide a comprehensive and up-to-date overview of the architecture, function and regulation of the STRIPAK complex and discuss key issues and future perspectives, linked with human diseases, which may form the basis of further research endeavors in this area. In particular, the investigation of bi-directional interactions between STRIPAK and other signaling pathways should elucidate upstream regulators and downstream targets as fundamental parts of a complex cellular network.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

scholarly journals X-ray and UV Radiation Damage of dsDNA/Protein Complexes

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3132
Author(s):  
Paweł Wityk ◽  
Dorota Kostrzewa-Nowak ◽  
Beata Krawczyk ◽  
Michał Michalik ◽  
Robert Nowak
Keyword(s):  
Dna Damage ◽  
Simple Model ◽  
Uv Radiation ◽  
Protein Complexes ◽  
Chemical Processes ◽  
Model Systems ◽  
Degradation Pathways ◽  
X Ray ◽  
Physico Chemical ◽  
Sensitization Process

Radiation and photodynamic therapies are used for cancer treatment by targeting DNA. However, efficiency is limited due to physico-chemical processes and the insensitivity of native nucleobases to damage. Thus, incorporation of radio- and photosensitizers into these therapies should increase both efficacy and the yield of DNA damage. To date, studies of sensitization processes have been performed on simple model systems, e.g., buffered solutions of dsDNA or sensitizers alone. To fully understand the sensitization processes and to be able to develop new efficient sensitizers in the future, well established model systems are necessary. In the cell environment, DNA tightly interacts with proteins and incorporating this interaction is necessary to fully understand the DNA sensitization process. In this work, we used dsDNA/protein complexes labeled with photo- and radiosensitizers and investigated degradation pathways using LC-MS and HPLC after X-ray or UV radiation.

scholarly journals Barth syndrome mutations that cause tafazzin complex lability

2011 ◽  
Vol 192 (3) ◽  
pp. 447-462 ◽  
Author(s):  
Steven M. Claypool ◽  
Kevin Whited ◽  
Santi Srijumnong ◽  
Xianlin Han ◽  
Carla M. Koehler
Keyword(s):  
Mitochondrial Function ◽  
Protein Complexes ◽  
Barth Syndrome ◽  
Human Diseases ◽  
Intermembrane Space ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Low Levels ◽  
Tafazzin Gene ◽  
Mutant Polypeptides

Deficits in mitochondrial function result in many human diseases. The X-linked disease Barth syndrome (BTHS) is caused by mutations in the tafazzin gene TAZ1. Its product, Taz1p, participates in the metabolism of cardiolipin, the signature phospholipid of mitochondria. In this paper, a yeast BTHS mutant tafazzin panel is established, and 18 of the 21 tested BTHS missense mutations cannot functionally replace endogenous tafazzin. Four BTHS mutant tafazzins expressed at low levels are degraded by the intermembrane space AAA (i-AAA) protease, suggesting misfolding of the mutant polypeptides. Paradoxically, each of these mutant tafazzins assembles in normal protein complexes. Furthermore, in the absence of the i-AAA protease, increased expression and assembly of two of the BTHS mutants improve their function. However, the BTHS mutant complexes are extremely unstable and accumulate as insoluble aggregates when disassembled in the absence of the i-AAA protease. Thus, the loss of function for these BTHS mutants results from the inherent instability of the mutant tafazzin complexes.

scholarly journals Maintenance of Yeast Genome Integrity by RecQ Family DNA Helicases

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 205 ◽  
Author(s):  
Sonia Vidushi Gupta ◽  
Kristina Hildegard Schmidt
Keyword(s):  
Genome Instability ◽  
Dna Helicase ◽  
Model Systems ◽  
Yeast Cells ◽  
Genome Integrity ◽  
Yeast Genome ◽  
Physical Interaction ◽  
Recq Helicase ◽  
Recq Helicases ◽  
Domain Structures

With roles in DNA repair, recombination, replication and transcription, members of the RecQ DNA helicase family maintain genome integrity from bacteria to mammals. Mutations in human RecQ helicases BLM, WRN and RecQL4 cause incurable disorders characterized by genome instability, increased cancer predisposition and premature adult-onset aging. Yeast cells lacking the RecQ helicase Sgs1 share many of the cellular defects of human cells lacking BLM, including hypersensitivity to DNA damaging agents and replication stress, shortened lifespan, genome instability and mitotic hyper-recombination, making them invaluable model systems for elucidating eukaryotic RecQ helicase function. Yeast and human RecQ helicases have common DNA substrates and domain structures and share similar physical interaction partners. Here, we review the major cellular functions of the yeast RecQ helicases Sgs1 of Saccharomyces cerevisiae and Rqh1 of Schizosaccharomyces pombe and provide an outlook on some of the outstanding questions in the field.

scholarly journals Epigenetic reader complexes of the human malaria parasite, Plasmodium falciparum

2019 ◽  
Vol 47 (22) ◽  
pp. 11574-11588 ◽  
Author(s):  
Wieteke Anna Maria Hoeijmakers ◽  
Jun Miao ◽  
Sabine Schmidt ◽  
Christa Geeke Toenhake ◽  
Sony Shrestha ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Complexes ◽  
Human Malaria Parasite ◽  
Phd Finger ◽  
Finger Protein ◽  
Binding Preference ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Eukaryotic Organisms ◽  
Interaction Proteomics

Abstract Epigenetic regulatory mechanisms are central to the development and survival of all eukaryotic organisms. These mechanisms critically depend on the marking of chromatin domains with distinctive histone tail modifications (PTMs) and their recognition by effector protein complexes. Here we used quantitative proteomic approaches to unveil interactions between PTMs and associated reader protein complexes of Plasmodium falciparum, a unicellular parasite causing malaria. Histone peptide pull-downs with the most prominent and/or parasite-specific PTMs revealed the binding preference for 14 putative and novel reader proteins. Amongst others, they highlighted the acetylation-level-dependent recruitment of the BDP1/BDP2 complex and identified an PhD-finger protein (PHD 1, PF3D7_1008100) that could mediate a cross-talk between H3K4me2/3 and H3K9ac marks. Tagging and interaction proteomics of 12 identified proteins unveiled the composition of 5 major epigenetic complexes, including the elusive TBP-associated-factor complex as well as two distinct GCN5/ADA2 complexes. Furthermore, it has highlighted a remarkable degree of interaction between these five (sub)complexes. Collectively, this study provides an extensive inventory of PTM-reader interactions and composition of epigenetic complexes. It will not only fuel further explorations of gene regulation amongst ancient eukaryotes, but also provides a stepping stone for exploration of PTM-reader interactions for antimalarial drug development.

scholarly journals Dissecting the Fine Details of Assembly of aT = 3 Phage Capsid

2005 ◽  
Vol 6 (2) ◽  
pp. 119-125 ◽  
Author(s):  
P. G. Stockley ◽  
A. E. Ashcroft ◽  
S. Francese ◽  
G. S. Thompson ◽  
N. A. Ranson ◽  
...  
Keyword(s):  
Rna Binding ◽  
Protein Complexes ◽  
Model Systems ◽  
Replicase Gene ◽  
Nmr Studies ◽  
Partial Explanation ◽  
Stem Loop ◽  
Assembly Pathway

The RNA bacteriophages represent ideal model systems in which to probe the detailed assembly pathway for the formation of aT = 3 quasi-equivalent capsid. For MS2, the assembly reaction can be probedin vitrousing acid disassembled coat protein subunits and a short (19 nt) RNA stem-loop that acts as the translational operator of the replicase gene and leads to sequence-specific sequestration and packaging of the cognate phage RNAin vivo. Reassembly reactions can be initiated by mixing these components at neutral pH. The molecular basis of the sequence-specific RNA–protein interaction is now well understood. Recent NMR studies on the protein demonstrate extensive mobility in the loops of the polypeptide that alter their conformations to form the quasi-equivalent conformers of the final capsid. It seems reasonable to assume that RNA binding results in reduction of this flexibility. However, mass spectrometry suggests that these RNA–protein complexes may only provide one type of quasi-equivalent capsid building block competent to form five-fold axes but not the full shell. Work with longer RNAs suggests that the RNA may actively template the assembly pathway providing a partial explanation of how conformers are selected in the growing shell.

Raf promotes dimerization of the Ras G-domain with increased allosteric connections

2020 ◽  
Author(s):  
Morgan Packer ◽  
Jillian A. Parker ◽  
Jean K. Chung ◽  
Zhenlu Li ◽  
Young Kwang Lee ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Lipid Bilayers ◽  
Md Simulations ◽  
Size Exclusion ◽  
Supported Lipid Bilayers ◽  
Erk Pathway ◽  
Signaling Complex ◽  
Macromolecular Assembly ◽  
High Affinity ◽  
Exclusion Chromatography

AbstractRas dimerization is critical for Raf activation, yet Ras alone does not dimerize. Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics (MD) simulations show robust allosteric connections linking the two Raf-RBD D113 residues, located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 Å apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway.

scholarly journals Prioritizing protein complexes implicated in human diseases by network optimization

2014 ◽  
Vol 8 (Suppl 1) ◽  
pp. S2 ◽  
Author(s):  
Yong Chen ◽  
Thibault Jacquemin ◽  
Shuyan Zhang ◽  
Rui Jiang
Keyword(s):  
Network Optimization ◽  
Protein Complexes ◽  
Human Diseases

scholarly journals Expression of Polarity Genes in Human Cancer

2015 ◽  
Vol 14s3 ◽  
pp. CIN.S18964 ◽  
Author(s):  
Wan-Hsin Lin ◽  
Yan W. Asmann ◽  
Panos Z. Anastasiadis
Keyword(s):  
Protein Complexes ◽  
Human Cancer ◽  
Expression Profiles ◽  
Tumor Formation ◽  
Model Systems ◽  
Epithelial Homeostasis ◽  
Directed Cell Migration ◽  
Protein Functions ◽  
Cancer Types ◽  
Polarity Proteins

Polarity protein complexes are crucial for epithelial apical-basal polarity and directed cell migration. Since alterations of these processes are common in cancer, polarity proteins have been proposed to function as tumor suppressors or oncogenic promoters. Here, we review the current understanding of polarity protein functions in epithelial homeostasis, as well as tumor formation and progression. As most previous studies focused on the function of single polarity proteins in simplified model systems, we used a genomics approach to systematically examine and identify the expression profiles of polarity genes in human cancer. The expression profiles of polarity genes were distinct in different human tissues and classified cancer types. Additionally, polarity expression profiles correlated with disease progression and aggressiveness, as well as with identified cancer types, where specific polarity genes were commonly altered. In the case of Scribble, gene expression analysis indicated its common amplification and upregulation in human cancer, suggesting a tumor promoting function.

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