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Prediction of a common structural scaffold for proteasome lid, COP9-signalosome and eIF3 complexes
Hartmut Scheel, Kay Hofmann
BMC Bioinformatics , 2005, DOI: 10.1186/1471-2105-6-71
Abstract: During an exhaustive bioinformatical analysis of proteasome components, we detected multiple instances of tetratrico-peptide repeats (TPR) in the N-terminal region of most PCI proteins, suggesting that their homology is not restricted to the PCI domain. We also detected a previously unrecognized PCI domain in the eIF3 component eIF3k, a protein whose 3D-structure has been determined recently. By using profile-guided alignment techniques, we show that the structural elements found in eIF3k are most likely conserved in all PCI proteins, resulting in a structural model for the canonical PCI domain.Our model predicts that the homology domain PCI is not a true domain in the structural sense but rather consists of two subdomains: a C-terminal 'winged helix' domain with a key role in PCI:PCI interaction, preceded by a helical repeat region. The TPR-like repeats detected in the N-terminal region of PCI proteins most likely form an uninterrupted extension of the repeats found within the PCI domain boundaries. This model allows an interpretation of several puzzling experimental results.In eukaryotic organisms, there exist at least three distinct multi-protein assemblies that are jointly referred to as 'PCI complexes' [1] and have a similar subunit architecture despite their fundamentally different function: i) the proteasome lid, a subcomplex of the 19S proteasome regulator and the 26S proteasome, ii) the COP9 signalosome or CSN complex, and iii) the eukaryotic translation initiation factor eIF3. As a common feature, these complexes are composed of multiple subunits harbouring the PCI domain, named after the three participating complexes [2], sometimes also referred to as the PINT domain [3]. Other subunits of these complexes are characterized by a second shared homology domain called MPN (Mpr1-Pad1 N-terminal) [2,3].Among these complexes, the proteasome lid and the CSN share a particular degree of analogy. Both complexes consist of eight core subunits, six of them of the PCI
MPN+, a putative catalytic motif found in a subset of MPN domain proteins from eukaryotes and prokaryotes, is critical for Rpn11 function
Vered Maytal-Kivity, Noa Reis, Kay Hofmann, Michael H Glickman
BMC Biochemistry , 2002, DOI: 10.1186/1471-2091-3-28
Abstract: We have identified a sequence motif, termed the MPN+ motif, which is highly conserved in a subset of MPN domain proteins such as Rpn11 and Csn5/Jab1, but is not present outside of this subfamily. The MPN+ motif consists of five polar residues that resemble the active site residues of hydrolytic enzyme classes, particularly that of metalloproteases. By using site-directed mutagenesis, we show that the MPN+ residues are important for the function of Rpn11, while a highly conserved Cys residue outside of the MPN+ motif is not essential. Single amino acid substitutions in MPN+ residues all show similar phenotypes, including slow growth, sensitivity to temperature and amino acid analogs, and general proteasome-dependent proteolysis defects.The MPN+ motif is abundant in certain MPN-domain proteins, including newly identified proteins of eukaryotes, bacteria and archaea thought to act outside of the traditional large PCI/MPN complexes. The putative catalytic nature of the MPN+ motif makes it a good candidate for a pivotal enzymatic function, possibly a proteasome-associated deubiquitinating activity and a CSN-associated Nedd8/Rub1-removing activity.Many regulatory proteins are removed from the cell in a timely and specific manner by a large multi subunit enzyme called the proteasome [1,2]. For proteins to be recognized by the proteasome, they are usually first covalently attached to a polyubiquitin chain via a cascade of ubiquitinating enzymes. This ubiquitination process is reversible. Specific cysteine proteases known as DUBs (deubiquitinating enzymes) can hydrolyze the amide bond between the Carboxy-terminus of ubiquitin and an amino group on the substrate [3,4]. Proteolysis takes place within the 20S core particle (CP) of the proteasome, while the 19S regulatory particle (RP) binds polyubiquitinated substrates, unfolds, and translocates them into the 20S CP for proteolysis. The discovery that the 19S regulatory particle of the proteasome (RP) can be separated into two
The Minimal Deneddylase Core of the COP9 Signalosome Excludes the Csn6 MPN? Domain
Elah Pick, Amnon Golan, Jacob Z. Zimbler, Liquan Guo, Yehonatan Sharaby, Tomohiko Tsuge, Kay Hofmann, Ning Wei
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043980
Abstract: The COP9 signalosome (CSN) is a eukaryotic protein complex, which regulates a wide range of biological processes mainly through modulating the cullin ubiquitin E3 ligases in the ubiquitin-proteasome pathway. The CSN possesses a highly conserved deneddylase activity that centers at the JAMM motif of the Csn5 subunit but requires other subunits in a complex assembly. The classic CSN is composed of 8 subunits (Csn1–8), yet in several Ascomycota, the complex is smaller and lacks orthologs for a few CSN subunits, but nevertheless contains a conserved Csn5. This feature makes yeast a powerful model to determine the minimal assemblage required for deneddylation activity. Here we report, that Csi1, a diverged S. cerevisiae CSN subunit, displays significant homology with the carboxyl terminal domain of the canonical Csn6, but lacks the amino terminal MPN- domain. Through the comparative and experimental analyses of the budding yeast and the mammalian CSNs, we demonstrate that the MPN? domain of the canonical mouse Csn6 is not part of the CSN deneddylase core. We also show that the carboxyl domain of Csn6 has an indispensable role in maintaining the integrity of the CSN complex. The CSN complex assembled with the carboxyl fragment of Csn6, despite its lack of an MPN? domain, is fully active in deneddylation of cullins. We propose that the budding yeast Csi1 is a functional equivalent of the canonical Csn6, and thus the composition of the CSN across phyla is more conserved than hitherto appreciated.
Quod erat demonstrandum? The mystery of experimental validation of apparently erroneous computational analyses of protein sequences
Lakshminarayan M Iyer, L Aravind, Peer Bork, Kay Hofmann, Arcady R Mushegian, Igor B Zhulin, Eugene V Koonin
Genome Biology , 2001, DOI: 10.1186/gb-2001-2-12-research0051
Abstract: We analyzed six cases where application of novel or conventional computational methods for protein sequence and structure analysis led to non-trivial predictions that were subsequently supported by direct experiments. We show that, on all six occasions, the original prediction was unjustified, and in at least three cases, an alternative, well-supported computational prediction, incompatible with the original one, could be derived. The most unusual cases involved the identification of an archaeal cysteinyl-tRNA synthetase, a dihydropteroate synthase and a thymidylate synthase, for which experimental verifications of apparently erroneous computational predictions were reported. Using sequence-profile analysis, multiple alignment and secondary-structure prediction, we have identified the unique archaeal 'cysteinyl-tRNA synthetase' as a homolog of extracellular polygalactosaminidases, and the 'dihydropteroate synthase' as a member of the β-lactamase-like superfamily of metal-dependent hydrolases.In each of the analyzed cases, the original computational predictions could be refuted and, in some instances, alternative strongly supported predictions were obtained. The nature of the experimental evidence that appears to support these predictions remains an open question. Some of these experiments might signify discovery of extremely unusual forms of the respective enzymes, whereas the results of others could be due to artifacts.The availability of a large number of protein sequences, including complete protein sets encoded in diverse genomes, and the rapidly growing database of protein structures have already greatly impacted on our understanding of the evolution of protein structure and function [1,2]. This process has been aided by the development of powerful algorithms and sensitive computational tools for detecting sequence and structural similarities between proteins. In particular, methods that extract information from multiple alignments to construct various types of
Towards Answering, What Do We Know about Elementary Pre-Service Teachers’ Noticing Skills in Science? A Pre-Requisite to Prepare Them to Teach Responsively in Science Classrooms  [PDF]
Tejaswini Dalvi, Anna Hofmann
Creative Education (CE) , 2019, DOI: 10.4236/ce.2019.102027
Abstract: A teachers’ ability to notice and analyse the substance of student thinking, is an important feature of effective science teaching. To prepare new science teachers to attend to students’ thinking, it is important for teacher educators to first understand what novice teachers notice in science classrooms, what they associate with the idea of noticing and in what ways their noticing skills can progress. To study novice teachers’ noticing abilities, our study employs two different assessment tools, an open noticing assignment and a focused noticing task as pre and post assessments during a semester long science methods course. We report on a variety of noticing themes that highlight a wide variation in what the novice teachers perceive as important to notice in science classrooms. Pre-post analysis of these noticing themes suggests a shift in noticing from general classroom aspects towards noticing science specific aspects as science topics or concepts being discussed and students’ ideas about those. Using a mixed methods analysis lens for both tools, we present various sophistication levels of teacher noticing. These levels not just serve as an indicator of the PSTs’ noticing skills but also as a framework for educators to help PSTs develop responsive teaching strategies in elementary science classrooms.
The Tissue-Specific Rep8/UBXD6 Tethers p97 to the Endoplasmic Reticulum Membrane for Degradation of Misfolded Proteins
Louise Madsen, Franziska Kriegenburg, Andrea Vala, Diana Best, S?ren Prag, Kay Hofmann, Michael Seeger, Ian R. Adams, Rasmus Hartmann-Petersen
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025061
Abstract: The protein known as p97 or VCP in mammals and Cdc48 in yeast is a versatile ATPase complex involved in several biological functions including membrane fusion, protein folding, and activation of membrane-bound transcription factors. In addition, p97 plays a central role in degradation of misfolded secretory proteins via the ER-associated degradation pathway. This functional diversity of p97 depends on its association with various cofactors, and to further our understanding of p97 function it is important that these cofactors are identified and analyzed. Here, we isolate and characterize the human protein named Rep8 or Ubxd6 as a new cofactor of p97. Mouse Rep8 is highly tissue-specific and abundant in gonads. In testes, Rep8 is expressed in post-meiotic round spermatids, whereas in ovaries Rep8 is expressed in granulosa cells. Rep8 associates directly with p97 via its UBX domain. We show that Rep8 is a transmembrane protein that localizes to the ER membrane with its UBX domain facing the cytoplasm. Knock-down of Rep8 expression in human cells leads to a decreased association of p97 with the ER membrane and concomitantly a retarded degradation of misfolded ER-derived proteasome substrates. Thus, Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation.
Osteoporosis: A Disease of Men  [PDF]
Anu Garg, Samantha Kay
Health (Health) , 2018, DOI: 10.4236/health.2018.101005
Abstract: Objective: The goal of this study was to evaluate osteoporosis screening practices in male patients aged 70 and older. Methods: A survey-based study was carried out over six months at an academic primary care institution in the Midwest. Results: Seventy-nine male patients and fifteen primary care physicians were surveyed. Less than 10% of males recalled being screened for osteoporosis. Two-thirds of physicians reported regularly screening males for osteoporosis. Conclusion: Elderly male patients are overwhelmingly under-screened and undertreated for osteoporosis.
Neurocode-Tracking Based on Quantitative Fast Dynamic EEG Recording in Combination with Eye-Tracking  [PDF]
Wilfried Dimpfel, Hans Carlos Hofmann
World Journal of Neuroscience (WJNS) , 2014, DOI: 10.4236/wjns.2014.42013

Information processing within the brain relies on electro-chemical features. Electric events are accessible by recording of the EEG. These electric oscillations might be regarded as a neuronal code carrying information on important motor, cognitive and emotional events. A new approach of quantitative assessment of very short time epochs of 364 ms has been developed on the base of particularly defined frequency ranges and called “Neurocode-Tracking”. The new method was technically validated by the use of a signal generator and was found to correspond to classical quantitative EEG analysis except for some smudging during the transition from one frequency range to the next. Real data from a subject were obtained during relaxation and performance of three mental tasks. Data were time averaged for 180 s using the classical method and compared to data averaging during 16.4 s. Results were nearly identical with respect to spectral signatures showing the expected midline frontal theta increases during performance of three cognitive tests but not during relaxation. Collection of very short time epochs of 728 ms duration confirmed task dependent frontal theta increases, most prominent during calculation performance test (CPT), less during d2-concentration and memory test, none during relaxation. Finally, the new technique was combined with eye-tracking. Capture of the EEG mapping video of Neurocode-Tracking and synchronization with the gaze overlay video by starting recording with an audio signal (gong) allowed a match of gazes precisely with the corresponding electric events. Use of this technical combination in research will hopefully lead to a new understanding of spectral signatures of electric activity called enkephaloglyphs.

Supply Chain Differentiation: Background, Concept and Examples  [PDF]
Erik Hofmann, Stephan Knébel
Journal of Service Science and Management (JSSM) , 2016, DOI: 10.4236/jssm.2016.92020
Abstract: The purpose of this paper is to provide new evidence in the field of supply chain differentiation. It aims to combine insights of supply chain management with the service dominant logic to connect fundamental customer requirements with supply chain decision-making. The paper claims to provide a framework that brings together the most relevant factors in the context of supply chain differentiation. The contents of the framework were applied as source to develop a generic decision support flowchart for supply chain executives. From the perspective of “test consumers”—supplemented with secondary data—two cases were examined. The cases provide insights for supply chain differentiation approaches of Adidas and Lego®. The crucial factor to link customer requirements with supply chain settings turned out to be the magnitude of customer co-creation along the value chain under consideration of synergies across the channels. The framework provides the opportunity to structure the complex multi-criteria decision problem constituted by supply chain differentiation. The paper provides helpful insights that could be used as starting point for the development of several industry specific decision-finding models or applications in supply chain differentiation.
Difficult-to-Treat-Depression and GPs’ Role: Perceptions of Psychiatry Registrars  [PDF]
Kay M. Jones, Leon Piterman
Open Journal of Psychiatry (OJPsych) , 2014, DOI: 10.4236/ojpsych.2014.44037
Abstract: Introduction: For patients, GPs are the most accessible medical resource in the community and are the gatekeepers to other community resources including psychiatrists. Qualifying as a psychiatrist in Australia involves completing a five-year training program that includes rotations in hospitals and community settings. The aims of this research were to 1) explore psychiatry registrars’ perceptions of difficult-to-treat-depression (DTTD) and 2) what they thought about the GPs’ role in this regard. Methods: A semi-structured interview schedule comprising six questions was used; 10 psychiatry registrars (6 females, 4 males) participated in a one-and-half-hour focus group. All were in their final year of training and undertaking a training post in a public hospital in Melbourne, Australia. Data were analysed using the Framework Method. Findings: Similar to GPs and GP trainees, psychiatry registrars’ perceptions and understanding of DTTD varied. While acknowledging limited experience in diagnosis and management, issues important to them included the utility of labels such as DTTD; patients distressed because of another diagnosis, substance abuse and/or life problems, the importance of accurate histories and notes, cost and limited availability of services particularly in the private sector, prescribing regimens, referring to allied health professionals, and suggesting/prescribing non pharmacological and/or complementary treatment. Also what was of concern was communication, both between health professionals and between health professionals and patients. Consensus was that treating depression in general practice is one of the hardest things for GPs to manage but there was value in using mental health plans. Discussion and Conclusion: While this cohort was small in number with limited experience, this study is the first to contribute to the literature that provides some insight into psychiatry registrars’ experiences and perceptions of DTTD. Outcomes may have implications for thepsychiatry training program and GPs who diagnose and manage patients with mental health problems.
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