876 research outputs found
QnAs with Susan L. Lindquist
No full textPrions defy molecular biology’s central dogma. Misfolded proteins that self-perpetuate, prions were first isolated in the early 1980s as the cause of a fatal sheep disease called scrapie. Since then, prions have been implicated in human neurodegenerative diseases, composing a rogue’s gallery of deadly disease agents. Susan Lindquist, a member of the National Academy of Sciences and a professor of biology at the Massachusetts Institute of Technology’s Whitehead Institute for Biomedical Research, has found that prions may have a little-appreciated positive side. Lindquist casts these seeming biochemical misfits in a surprising evolutionary role: Her studies have revealed that prions might help cells adapt to a host of environmental pressures. Lindquist explains this still-contentious idea to PNAS readers
How Do We Pass Our Traits to Our Offspring?
No full textDr. Susan Lindquist talks to students about evolution, and proteins, and drug resistance fungi as part of the 2011 Roy Moon Distinguished Lectureship in ScienceAngelo State Universit
Using Simple Organisms to help in complex disease processes
No full textDr. Susan Lindquist talks about how neurological diseases happen and why they happen as part of the 2011 Roy E. Moon Distinguished Lectureship in ScienceAngelo State UniversityAngelo State UniversityWest Texas Medical Associate
A Day with a Leading Scientist: Susan Lindquist
No full textIn the spring semester of 2007, the honor of the 21st Annual Volwiler Lecture was given to Massachusetts Institute of Technology (MIT) professor of biology and investigator of the Howard Hughes Medical Institute, Susan Lindquist. She is a distinguished scientist in the field of biomedical research. Her study is on protein folding, a basic and essential function carried out by living cells. Interestingly, her research overlaps with studies on evolution, neurological diseases, and cancer, all of which impact society greatly
Protein Folding Sculpting Evolutionary Change
No full textOur work suggests that the forces that govern protein folding exert a profound effect on how genotypes are translated into phenotypes and that this in turn has strong effects on evolutionary processes. Molecular chaperones, also known as “heat-shock proteins” (Hsps), promote the correct folding and maturation of many other proteins in the cell. Hsp90 is an abundant and highly specialized chaperone that works on a particularly interesting group of client proteins: metastable signal transducers that are key regulators of a broad spectrum of biological processes. Such proteins often have evolved to finish folding only when they have received a specific signal, such as the binding of a ligand or a posttranslational modification. Importantly, the folding of Hsp90 clients is particularly sensitive to changes in the external and internal environment of the cell. Therefore, Hsp90 is uniquely positioned to couple environmental contingencies to the evolution of new traits. Our work has helped to define two mechanisms by which Hsp90 might influence the acquisition of new phenotypes. First, by robustly maintaining signaling pathways, Hsp90 can buffer the effects of mutations in those pathways, allowing the storage of cryptic genetic variation that is released by stress. In this case, when the Hsp90 buffer is compromised by environmental stress, new traits appear. These traits can also be assimilated, so that they become manifest even in the absence of stress, when genetic recombination and selection enrich causative variants in subsequent generations. Second, Hsp90 can potentiate the effects of genetic variation, allowing new mutations to produce immediate phenotypes. In this case, when Hsp90 function is compromised, new traits are lost. These traits can also be assimilated, so that they are maintained under environmental stress, but this is achieved through new mutations. We have discovered these powerful evolutionary mechanisms in fruit flies, mustard plants, and fungi, but expect them to operate in all eukaryotes. Another line of work relating protein folding to the evolution of new traits involves protein-based hereditary elements known as prions. These produce changes in phenotype through heritable, self-perpetuating changes in protein conformation. Because changes in protein homeostasis occur with environmental stress, prions can be cured or induced by stress, creating heritable new phenotypes that depend on the genetic variation present in the organism. Both prions and Hsp90 provide plausible mechanisms for allowing genetic diversity and fluctuating environments to fuel the pace of evolutionary change. The multiple mechanisms by which protein folding can influence the evolution of new traits provide both a new paradigm for understanding rapid, stepwise evolution and a framework for targeted therapeutic interventions.United States. National Institutes of Health (grant R01GM025874)Broad Institute of MIT and HarvardG. Harold and Leila Y. Mathers FoundationHoward Hughes Medical Institut
Three quite different things that matter to me
No full textI'm grateful to be asked to comment on cell biology and the next 50 years. There is much to say. But let me focus on just three quite different things that particularly matter to me. 1. SOME ADVICE TO THE YOUNG
I am somewhat abashed to say, right at the start of this piece, that I don't think of myself as a cell biologist—any more than as a geneticist or biochemist. One of the great glories of our field is that it is bursting the dam and flooding the plains. Cell biologists investigate not just the cell but also the whole organism and its ecosystem, and peer, with revelation, at individual molecules
Unraveling infectious structures, strain variants and species barriers for the yeast prion [PSI+]
No full textPrions are proteins that can access multiple conformations, at least one of which is beta-sheet rich, infectious and self-perpetuating in nature. These infectious proteins show several remarkable biological activities, including the ability to form multiple infectious prion conformations, also known as strains or variants, encoding unique biological phenotypes, and to establish and overcome prion species (transmission) barriers. In this Perspective, we highlight recent studies of the yeast prion [PSI+], using various biochemical and structural methods, that have begun to illuminate the molecular mechanisms by which self-perpetuating prions encipher such biological activities. We also discuss several aspects of prion conformational change and structure that remain either unknown or controversial, and we propose approaches to accelerate the understanding of these enigmatic, infectious conformers
A heritable switch in carbon source utilization driven by an unusual yeast prion
No full textSeveral well-characterized fungal proteins act as prions, proteins capable of multiple conformations, each with different activities, at least one of which is self-propagating. Through such self-propagating changes in function, yeast prions act as protein-based elements of phenotypic inheritance. We report a prion that makes cells resistant to the glucose-associated repression of alternative carbon sources, [GAR[superscript +]] (for “resistant to glucose-associated repression,” with capital letters indicating dominance and brackets indicating its non-Mendelian character). [GAR[superscript +]] appears spontaneously at a high rate and is transmissible by non-Mendelian, cytoplasmic inheritance. Several lines of evidence suggest that the prion state involves a complex between a small fraction of the cellular complement of Pma1, the major plasma membrane proton pump, and Std1, a much lower-abundance protein that participates in glucose signaling. The Pma1 proteins from closely related Saccharomyces species are also associated with the appearance of [GAR[superscript +]]. This allowed us to confirm the relationship between Pma1, Std1, and [GAR[superscript +]] by establishing that these proteins can create a transmission barrier for prion propagation and induction in Saccharomyces cerevisiae. The fact that yeast cells employ a prion-based mechanism for heritably switching between distinct carbon source utilization strategies, and employ the plasma membrane proton pump to do so, expands the biological framework in which self-propagating protein-based elements of inheritance operate.United States. National Institutes of Health (grant GM25874
- …
