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Cold Spring Harbor Perspectives in Biology

Francesc R Garcia-Gonzalo, Jeremy F Reiter
Cilia are plasma membrane protrusions that act as cellular propellers or antennae. To perform these functions, cilia must maintain a composition distinct from those of the contiguous cytosol and plasma membrane. The specialized composition of the cilium depends on the ciliary gate, the region at the ciliary base separating the cilium from the rest of the cell. The ciliary gate's main structural features are electron dense struts connecting microtubules to the adjacent membrane. These structures include the transition fibers, which connect the distal basal body to the base of the ciliary membrane, and the Y-links, which connect the proximal axoneme and ciliary membrane within the transition zone...
October 21, 2016: Cold Spring Harbor Perspectives in Biology
Thomas D Loreng, Elizabeth F Smith
The motile cilium is a complex organelle that is typically comprised of a 9+2 microtubule skeleton; nine doublet microtubules surrounding a pair of central singlet microtubules. Like the doublet microtubules, the central microtubules form a scaffold for the assembly of protein complexes forming an intricate network of interconnected projections. The central microtubules and associated structures are collectively referred to as the central apparatus (CA). Studies using a variety of experimental approaches and model organisms have led to the discovery of a number of highly conserved protein complexes, unprecedented high-resolution views of projection structure, and new insights into regulation of dynein-driven microtubule sliding...
October 21, 2016: Cold Spring Harbor Perspectives in Biology
Jessica G Perez, Jessica C Stark, Michael C Jewett
Cell-free protein synthesis (CFPS) technologies have enabled inexpensive and rapid recombinant protein expression. Numerous highly active CFPS platforms are now available and have recently been used for synthetic biology applications. In this review, we focus on the ability of CFPS to expand our understanding of biological systems and its applications in the synthetic biology field. First, we outline a variety of CFPS platforms that provide alternative and complementary methods for expressing proteins from different organisms, compared with in vivo approaches...
October 14, 2016: Cold Spring Harbor Perspectives in Biology
Steven A Benner, Nilesh B Karalkar, Shuichi Hoshika, Roberto Laos, Ryan W Shaw, Mariko Matsuura, Diego Fajardo, Patricia Moussatche
In its "grand challenge" format in chemistry, "synthesis" as an activity sets out a goal that is substantially beyond current theoretical and technological capabilities. In pursuit of this goal, scientists are forced across uncharted territory, where they must answer unscripted questions and solve unscripted problems, creating new theories and new technologies in ways that would not be created by hypothesis-directed research. Thus, synthesis drives discovery and paradigm changes in ways that analysis cannot...
September 23, 2016: Cold Spring Harbor Perspectives in Biology
David R Mitchell
Anton van Leeuwenhoek's startling microscopic observations in the 1600s first stimulated fascination with the way that cells use cilia to generate currents and to swim in a fluid environment. Research in recent decades has yielded deep knowledge about the mechanical and biochemical nature of these organelles but only opened a greater fascination about how such beautifully intricate and multifunctional structures arose during evolution. Answers to this evolutionary puzzle are not only sought to satisfy basic curiosity, but also, as stated so eloquently by Dobzhansky (Am Zool 4: 443 [1964]), because "nothing in biology makes sense except in the light of evolution...
September 23, 2016: Cold Spring Harbor Perspectives in Biology
S E Sanchez, S A Kay
The plant circadian clock allows organisms to anticipate the predictable changes in the environment by adjusting their developmental and physiological traits. In the last few years, it was determined that responses known to be regulated by the oscillator are also able to modulate clock performance. These feedback loops and their multilayer communications create a complex web, and confer on the clock network a role that exceeds the measurement of time. In this article, we discuss the current knowledge of the wiring of the clock, including the interplay with metabolism, hormone, and stress pathways in the model species Arabidopsis thaliana We outline the importance of this system in crop agricultural traits, highlighting the identification of natural alleles that alter the pace of the timekeeper...
September 23, 2016: Cold Spring Harbor Perspectives in Biology
Søren T Christensen, Stine K Morthorst, Johanne B Mogensen, Lotte B Pedersen
Since the beginning of the millennium, research in primary cilia has revolutionized our way of understanding how cells integrate and organize diverse signaling pathways during vertebrate development and in tissue homeostasis. Primary cilia are unique sensory organelles that detect changes in their extracellular environment and integrate and transmit signaling information to the cell to regulate various cellular, developmental, and physiological processes. Many different signaling pathways have now been shown to rely on primary cilia to function properly, and mutations that lead to ciliary dysfunction are at the root of a pleiotropic group of diseases and syndromic disorders called ciliopathies...
September 16, 2016: Cold Spring Harbor Perspectives in Biology
Andrew P Hinck, Thomas D Mueller, Timothy A Springer
We review the evolution and structure of members of the transforming growth factor β (TGF-β) family, antagonistic or agonistic modulators, and receptors that regulate TGF-β signaling in extracellular environments. The growth factor (GF) domain common to all family members and many of their antagonists evolved from a common cystine knot growth factor (CKGF) domain. The CKGF superfamily comprises six distinct families in primitive metazoans, including the TGF-β and Dan families. Compared with Wnt/Frizzled and Notch/Delta families that also specify body axes, cell fate, tissues, and other families that contain CKGF domains that evolved in parallel, the TGF-β family was the most fruitful in evolution...
September 16, 2016: Cold Spring Harbor Perspectives in Biology
Takashi Ishikawa
The axoneme is the main extracellular part of cilia and flagella in eukaryotes. It consists of a microtubule cytoskeleton, which normally comprises nine doublets. In motile cilia, dynein ATPase motor proteins generate sliding motions between adjacent microtubules, which are integrated into a well-orchestrated beating or rotational motion. In primary cilia, there are a number of sensory proteins functioning on membranes surrounding the axoneme. In both cases, as the study of proteomics has elucidated, hundreds of proteins exist in this compartmentalized biomolecular system...
September 6, 2016: Cold Spring Harbor Perspectives in Biology
Heiko Braak, Kelly Del Tredici
Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer's disease (AD) and Parkinson's disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and α-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown...
August 31, 2016: Cold Spring Harbor Perspectives in Biology
Alice Meunier, Juliette Azimzadeh
Many animal cells assemble single cilia involved in motile and/or sensory functions. In contrast, multiciliated cells (MCCs) assemble up to 300 motile cilia that beat in a coordinate fashion to generate a directional fluid flow. In the human airways, the brain, and the oviduct, MCCs allow mucus clearance, cerebrospinal fluid circulation, and egg transportation, respectively. Impairment of MCC function leads to chronic respiratory infections and increased risks of hydrocephalus and female infertility. MCC differentiation during development or repair involves the activation of a regulatory cascade triggered by the inhibition of Notch activity in MCC progenitors...
August 31, 2016: Cold Spring Harbor Perspectives in Biology
Apirat Chaikuad, Alex N Bullock
Stimulation of the transforming growth factor β (TGF-β) family receptors activates an intracellular phosphorylation-dependent signaling cascade that culminates in Smad transcriptional activation and turnover. Structural studies have identified a number of allosteric mechanisms that control the localization, conformation, and oligomeric state of the receptors and Smads. Such mechanisms dictate the ordered binding of substrate and adaptor proteins that determine the directionality of the signaling process. Activation of the pathway has been illustrated by the various structures of the receptor-activated Smads (R-Smads) with SARA, Smad4, and YAP, respectively, whereas mechanisms of down-regulation have been elucidated by the structural complexes of FKBP12, Ski, and Smurf1...
August 22, 2016: Cold Spring Harbor Perspectives in Biology
Stephen M King
Axonemal dyneins form the inner and outer rows of arms associated with the doublet microtubules of motile cilia. These enzymes convert the chemical energy released from adenosine triphosphate (ATP) hydrolysis into mechanical work by causing the doublets to slide with respect to each other. Dyneins form two major groups based on the number of heavy-chain motors within each complex. In addition, these enzymes contain other components that are required for assembly of the complete particles and/or for the regulation of motor function in response to phosphorylations status, ligands such as Ca(2+), changes in cellular redox state and which also apparently monitor and respond to the mechanical state or curvature in which any given motor finds itself...
August 15, 2016: Cold Spring Harbor Perspectives in Biology
Anna Lechner, Elizabeth Brunk, Jay D Keasling
This review highlights state-of-the-art procedures for heterologous small-molecule biosynthesis, the associated bottlenecks, and new strategies that have the potential to accelerate future accomplishments in metabolic engineering. We emphasize that a combination of different approaches over multiple time and size scales must be considered for successful pathway engineering in a heterologous host. We have classified these optimization procedures based on the "system" that is being manipulated: transcriptome, translatome, proteome, or reactome...
August 15, 2016: Cold Spring Harbor Perspectives in Biology
Ronald K H Liem
This review discusses the spectrin superfamily of proteins that function to connect cytoskeletal elements to each other, the cell membrane, and the nucleus. The signature domain is the spectrin repeat, a 106-122-amino-acid segment comprising three α-helices. α-actinin is considered to be the ancestral protein and functions to cross-link actin filaments. It then evolved to generate spectrin and dystrophin that function to link the actin cytoskeleton to the cell membrane, as well as the spectraplakins and plakins that link cytoskeletal elements to each other and to junctional complexes...
October 3, 2016: Cold Spring Harbor Perspectives in Biology
Gökhan S Hotamisligil, Roger J Davis
Stress-signaling pathways are evolutionarily conserved and play an important role in the maintenance of homeostasis. These pathways are also critical for adaptation to new cellular environments. The endoplasmic reticulum (ER) unfolded protein response (UPR) is activated by biosynthetic stress and leads to a compensatory increase in ER function. The JNK and p38 MAPK signaling pathways control adaptive responses to intracellular and extracellular stresses, including environmental changes such as UV light, heat, and hyperosmotic conditions, and exposure to inflammatory cytokines...
October 3, 2016: Cold Spring Harbor Perspectives in Biology
Danielly C F Costa, Guilherme A P de Oliveira, Elio A Cino, Iaci N Soares, Luciana P Rangel, Jerson L Silva
Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function...
October 3, 2016: Cold Spring Harbor Perspectives in Biology
Rainer Breitling, Eriko Takano
The diversity and natural modularity of their biosynthetic pathways has turned natural products into attractive, but challenging, targets for synthetic biology approaches. Here, we discuss the current state of the field, highlighting recent advances and remaining bottlenecks. Global genomic assessments of natural product biosynthetic capacities across large parts of microbial diversity provide a first survey of the available natural parts libraries and identify evolutionary design rules for further engineering...
October 3, 2016: Cold Spring Harbor Perspectives in Biology
E Magda Barbu, Kyle C Cady, Bolyn Hubby
For more than a century, bacteriophage (or phage) research has enabled some of the most important discoveries in biological sciences and has equipped scientists with many of the molecular biology tools that have advanced our understanding of replication, maintenance, and expression of genetic material. Phages have also been recognized and exploited as natural antimicrobial agents and nanovectors for gene therapy, but their potential as therapeutics has not been fully exploited in Western medicine because of challenges such as narrow host range, bacterial resistance, and unique pharmacokinetics...
October 3, 2016: Cold Spring Harbor Perspectives in Biology
Caroline S Hill
The transforming growth factor-β (TGF-β) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications...
October 3, 2016: Cold Spring Harbor Perspectives in Biology
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