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Cold Spring Harbor Perspectives in Biology

Anne Wentink, Carmen Nussbaum-Krammer, Bernd Bukau
Aberrant protein aggregation is a defining feature of most neurodegenerative diseases. During pathological aggregation, key proteins transition from their native state to alternative conformations, which are prone to oligomerize into highly ordered fibrillar states. As part of the cellular quality control machinery, molecular chaperones can intervene at many stages of the aggregation process to inhibit or reverse aberrant protein aggregation or counteract the toxicity associated with amyloid species. Although the action of chaperones is considered cytoprotective, essential housekeeping functions can be hijacked for the propagation and spreading of protein aggregates, suggesting the cellular protein quality control system constitutes a double-edged sword in neurodegeneration...
February 12, 2019: Cold Spring Harbor Perspectives in Biology
James Shorter, Daniel R Southworth
Hsp104 is a hexameric AAA+ ATPase and protein disaggregase found in yeast, which couples ATP hydrolysis to the dissolution of diverse polypeptides trapped in toxic preamyloid oligomers, phase-transitioned gels, disordered aggregates, amyloids, and prions. Hsp104 shows plasticity in disaggregating diverse substrates, but how its hexameric architecture operates as a molecular machine has remained unclear. Here, we highlight structural advances made via cryoelectron microscopy (cryo-EM) that enhance our mechanistic understanding of Hsp104 and other related AAA+ translocases...
February 11, 2019: Cold Spring Harbor Perspectives in Biology
David L Prole, Colin W Taylor
Inositol 1,4,5-trisphosphate receptors (IP3 Rs), by releasing Ca2+ from the endoplasmic reticulum (ER) of animal cells, allow Ca2+ to be redistributed from the ER to the cytosol or other organelles, and they initiate store-operated Ca2+ entry (SOCE). For all three IP3 R subtypes, binding of IP3 primes them to bind Ca2+ , which then triggers channel opening. We are now close to understanding the structural basis of IP3 R activation. Ca2+ -induced Ca2+ release regulated by IP3 allows IP3 Rs to regeneratively propagate Ca2+ signals...
February 11, 2019: Cold Spring Harbor Perspectives in Biology
Maximilian M Biebl, Johannes Buchner
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the maturation of a plethora of substrates ("clients"), including protein kinases, transcription factors, and E3 ubiquitin ligases, positioning Hsp90 as a central regulator of cellular proteostasis. Hsp90 undergoes large conformational changes during its ATPase cycle. The processing of clients by cytosolic Hsp90 is assisted by a cohort of cochaperones that affect client recruitment, Hsp90 ATPase function or conformational rearrangements in Hsp90...
February 11, 2019: Cold Spring Harbor Perspectives in Biology
Zlata Gvozdenov, Janhavi Kolhe, Brian C Freeman
Maintenance of a healthy and functional proteome in all cellular compartments is critical to cell and organismal homeostasis. Yet, our understanding of the proteostasis process within the nucleus is limited. Here, we discuss the identified roles of the major molecular chaperones Hsp90, Hsp70, and Hsp60 with client proteins working in diverse DNA-associated pathways. The unique challenges facing proteins in the nucleus are considered as well as the conserved features of the molecular chaperone system in facilitating DNA-linked processes...
February 11, 2019: Cold Spring Harbor Perspectives in Biology
Patrick G Needham, Christopher J Guerriero, Jeffrey L Brodsky
Misfolded proteins compromise cellular homeostasis. This is especially problematic in the endoplasmic reticulum (ER), which is a high-capacity protein-folding compartment and whose function requires stringent protein quality-control systems. Multiprotein complexes in the ER are able to identify, remove, ubiquitinate, and deliver misfolded proteins to the 26S proteasome for degradation in the cytosol, and these events are collectively termed ER-associated degradation, or ERAD. Several steps in the ERAD pathway are facilitated by molecular chaperone networks, and the importance of ERAD is highlighted by the fact that this pathway is linked to numerous protein conformational diseases...
January 22, 2019: Cold Spring Harbor Perspectives in Biology
Sofia Ahola, Thomas Langer, Thomas MacVicar
Mitochondria are metabolic hubs that use multiple proteases to maintain proteostasis and to preserve their overall quality. A decline of mitochondrial proteolysis promotes cellular stress and may contribute to the aging process. Mitochondrial proteases have also emerged as tightly regulated enzymes required to support the remarkable mitochondrial plasticity necessary for metabolic adaptation in a number of physiological scenarios. Indeed, the mutation and dysfunction of several mitochondrial proteases can cause specific human diseases with severe metabolic phenotypes...
January 22, 2019: Cold Spring Harbor Perspectives in Biology
G Elif Karagöz, Diego Acosta-Alvear, Peter Walter
Most of the secreted and plasma membrane proteins are synthesized on membrane-bound ribosomes on the endoplasmic reticulum (ER). They require engagement of ER-resident chaperones and foldases that assist in their folding and maturation. Since protein homeostasis in the ER is crucial for cellular function, the protein-folding status in the organelle's lumen is continually surveyed by a network of signaling pathways, collectively called the unfolded protein response (UPR). Protein-folding imbalances, or "ER stress," are detected by highly conserved sensors that adjust the ER's protein-folding capacity according to the physiological needs of the cell...
January 22, 2019: Cold Spring Harbor Perspectives in Biology
Justine Lempart, Ursula Jakob
Polyphosphate (polyP), an extremely simple polyanion, has long been known to be involved in a variety of different cellular processes, ranging from stress resistance, biofilm formation, and virulence in bacteria to bone mineralization, blood clotting, and mammalian target of rapamycin (mTOR) signaling in mammalian organisms. Our laboratory recently discovered a completely unexpected role of polyP as a stabilizing scaffold for β-sheet-containing protein-folding intermediates. This realization led us to investigate the effects of polyP on amyloidogenic processes and the novel concept that polyP might play a role in neurodegenerative diseases...
January 7, 2019: Cold Spring Harbor Perspectives in Biology
Nandhitha Uma Naresh, Cole M Haynes
The mitochondrial proteome encompasses more than a thousand proteins, which are encoded by the mitochondrial and nuclear genomes. Mitochondrial biogenesis and network health relies on maintenance of protein import pathways and the protein-folding environment. Cell-extrinsic or -intrinsic stressors that challenge mitochondrial proteostasis negatively affect organellar function. During conditions of stress, cells use impaired protein import as a sensor for mitochondrial dysfunction to activate a stress response called the mitochondrial unfolded protein response (UPRmt )...
January 7, 2019: Cold Spring Harbor Perspectives in Biology
Titus M Franzmann, Simon Alberti
Cells under stress must adjust their physiology, metabolism, and architecture to adapt to the new conditions. Most importantly, they must down-regulate general gene expression, but at the same time induce synthesis of stress-protective factors, such as molecular chaperones. Here, we investigate how the process of phase separation is used by cells to ensure adaptation to stress. We summarize recent findings and propose that the solubility of important translation factors is specifically affected by changes in physical-chemical parameters such temperature or pH and modulated by intrinsically disordered prion-like domains...
January 7, 2019: Cold Spring Harbor Perspectives in Biology
Joseph Lipsick
Proteins containing tyrosine kinase activity play critical roles in cancer signaling. Intracellular SRC-family kinases relay growth signals from numerous cell surface receptors and can be constitutively activated by oncogenic mutations, as can transmembrane growth factor receptors such as epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) that signal via their tyrosine kinase activity. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at the discovery of tyrosine kinases and the demonstration that the V-SRC protein encoded by Rous sarcoma virus was a tyrosine kinase...
February 1, 2019: Cold Spring Harbor Perspectives in Biology
Briana Van Treeck, Roy Parker
SUMMARYEukaryotic cells contain a large number of RNA-protein assemblies, generically referred to as ribonucleoprotein (RNP) granules. Such RNP granules include stress granules and P-bodies in the cytosol and the nucleolus, Cajal bodies, and paraspeckles in the nucleus. A variety of imaging approaches have been used to reveal different components, structural features, and dynamics of RNP granules. In this review, we discuss imaging approaches that have been used to study stress granules and the insights gained from these experiments...
February 1, 2019: Cold Spring Harbor Perspectives in Biology
Lydia Villa-Komaroff
Academic administration can be an extension of an academic career at the bench or it can run parallel to a career of discovery. To be an academic administrator at the executive level in a college or university generally requires advancement through the academic ranks to the professorial level. These positions include department chair, dean of a college, head of a center or institute, provost, senior research officer, and university or college president. Positions that can begin immediately after attaining a PhD or after a postdoctoral position include some assistant dean roles and positions in technology transfer, grants management, and laboratory management, among many others...
February 1, 2019: Cold Spring Harbor Perspectives in Biology
Christopher C Venters, Jung-Min Oh, Chao Di, Byung Ran So, Gideon Dreyfuss
SUMMARYRecent observations showed that nascent RNA polymerase II transcripts, pre-mRNAs, and noncoding RNAs are highly susceptible to premature 3'-end cleavage and polyadenylation (PCPA) from numerous intronic cryptic polyadenylation signals (PASs). The importance of this in gene regulation was not previously appreciated as PASs, despite their prevalence, were thought to be active in terminal exons at gene ends. Unexpectedly, antisense oligonucleotide interference with U1 snRNA base-pairing to 5' splice sites, which is necessary for U1 snRNP's (U1) function in splicing, caused widespread PCPA in metazoans...
February 1, 2019: Cold Spring Harbor Perspectives in Biology
Yfke Hager
The pharmaceutical industry spends billions each year on the clinical development of new medicines. Getting those products to the patients who will benefit from them requires an ability to convey the results of extensive clinical research programs to regulatory authorities, physicians, and payers. Employed by medical communications agencies, contract research organizations, and pharmaceutical companies, medical writers distill and translate complex clinical and scientific data to develop documentation spanning the entire pharmaceutical-product life cycle, from clinical development to registration and marketing...
January 2, 2019: Cold Spring Harbor Perspectives in Biology
Calvin M Schmidt, Christina D Smolke
SummaryIn addition to coding for protein sequences, RNA molecules encode a diverse set of gene-regulatory elements. RNA switches are one class of gene-regulatory elements that control protein expression in a manner that is dependent on the concentration of specific ligand molecules. These allosteric gene-regulatory elements have been shown as useful tools in engineering diverse cell types to display novel function. In particular, RNA switches have been used as genetically encoded biosensors and conditional controllers to direct cellular decisions based on the system's changing environment...
January 2, 2019: Cold Spring Harbor Perspectives in Biology
Chuangye Yan, Ruixue Wan, Yigong Shi
SUMMARYPrecursor messenger RNA (pre-mRNA) splicing is executed by the spliceosome. In the past 3 years, cryoelectron microscopy (cryo-EM) structures have been elucidated for a majority of the yeast spliceosomal complexes and for a few human spliceosomes. During the splicing reaction, the dynamic spliceosome has an immobile core of about 20 protein and RNA components, which are organized around a conserved splicing active site. The divalent metal ions, coordinated by U6 small nuclear RNA (snRNA), catalyze the branching reaction and exon ligation...
January 2, 2019: Cold Spring Harbor Perspectives in Biology
Steffen Preissler, David Ron
No abstract text is available yet for this article.
December 3, 2018: Cold Spring Harbor Perspectives in Biology
Zhipeng Lu, Howard Y Chang
SUMMARYRNA molecules are folded into structures and complexes to perform a wide variety of functions. Determination of RNA structures and their interactions is a fundamental problem in RNA biology. Most RNA molecules in living cells are large and dynamic, posing unique challenges to structure analysis. Here we review progress in RNA structure analysis, focusing on methods that use the "cross-link, proximally ligate, and sequence" principle for high-throughput detection of base-pairing interactions in living cells...
December 3, 2018: Cold Spring Harbor Perspectives in Biology
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