Susan Lindquist

Bio: Susan Lindquist is an academic researcher from Massachusetts Institute of Technology. The author has contributed to research in topics: Heat shock protein & Saccharomyces cerevisiae. The author has an hindex of 147, co-authored 440 publications receiving 81067 citations. Previous affiliations of Susan Lindquist include University of Illinois at Chicago & Howard Hughes Medical Institute.

Chaperone interaction assays and uses thereof

Abstract: In some aspects, the invention provides methods of identifying, detecting, and/or measuring protein-protein interactions. In some aspects, the invention provides methods of identifying and/or characterizing modulators of protein-protein interactions. In some aspects, the invention provides methods of identifying and/or characterizing modulators of protein activity, wherein the methods are based at least in part on measuring interaction between a chaperone and client protein. In some aspects, the invention provides methods for identifying and/or characterizing compounds and/or for assessing compound specificity, wherein the methods are based at least in part on measuring interaction between a chaperone and client protein. In some embodiments, a client protein is a kinase. In some embodiments, a compound is a kinase inhibitor. In some aspects, the invention provides methods of profiling kinase inhibitor specificity. In some aspects, the invention provides assay systems and/or reagents useful for performing one or more of the inventive methods. In some aspects, the invention provides newly identified targets of a variety of kinase inhibitors. In some aspect, the invention provides methods of inhibiting kinases identified herein as targets of certain kinase inhibitors. In some aspects, the invention provides methods of treating a disease, e.g., cancer, by inhibiting one or more kinase(s) newly identified as targets of certain kinase inhibitors.

Indazole derivatives and uses thereof

Abstract: The present invention provides novel compounds (e.g., compounds of Formula (I)), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits comprising the inventive compounds, or compositions thereof, for treating and/or preventing a fungal or protozoan infection, inhibiting the activity of a fungal or protozoan enzyme, killing a fungus or protozoon, or inhibiting the growth of a fungus or protozoon. The fungus may be a Candida species, Aspergillus species, or other pathogenic fungal species. The compounds of the invention may inhibit the activity of fungal or protozoan cytochrome b and/or fungal or protozoan Hsp90. The present invention also provides synthetic methods of the inventive compounds.

Self-perpetuating structural states in biology, disease, and genetics.

Abstract: Over the past half-century, the central dogma, in which DNA makes RNA makes protein, has dominated thinking in biology, with continuing refinements in understanding of DNA inheritance, gene expression, and macromolecular interactions. However, we have also witnessed the elucidation of epigenetic phenomena that violate conventional notions of inheritance. Protein-only inheritance involves the transmission of phenotypes by self-perpetuating changes in protein conformation. Proteins that constitute chromatin can also transmit heritable information, for example, via posttranslational modifications of histones. Both the transmission of phenotypes via the formation of protein conformations and the inheritance of chromatin states involve self-perpetuating assemblies of proteins, and there is evidence for some common structural features and conceptual frameworks between them. To foster interactions between researchers in these two fields, the National Academy of Sciences convened an Arthur M. Sackler Colloquium entitled “Self-Perpetuating Structural States in Biology, Disease, and Genetics” in Washington, DC, on March 22–24, 2002. Participants described new phenomenology and provided insights into fundamental mechanisms of protein and chromatin inheritance. Perhaps most surprising to attendees was emerging evidence that these unconventional modes of inheritance may be common. First described in studies of scrapie and other transmissible encephalopathies in mammals, prions were later shown to cause some classical phenotypes in yeast. In each case, an alternative protein conformation leads to formation of structures resembling amyloid fibers seen in human disease. How these are seeded has been elucidated by in vitro studies, leading to a satisfying picture of prion-like protein propagation. Other cases of prion inheritance have been discovered in genetic screens, which suggests that we are seeing only the tip of the iceberg. Indeed, it now appears that amyloid fiber formation is the default state for misfolded proteins, and fibrillar aggregates found in amyloidoses result from defects in the cellular machinery that prevents protein misfolding. Excitement also pervades the chromatin field, with new insights into how nucleosomes specify and maintain distinct chromatin states. Remarkably, a single modification of a histone tail residue underlies the distinction between euchromatin and heterochromatin, and even maintenance of DNA methylation can depend on histone tail modification. From insights such as these, we have begun to realize that the relationship between chromatin conformation and gene expression might have a simple basis. Genetic and biochemical approaches have begun to elucidate how histone-modifying enzymes and nonhistone structural proteins regulate chromatin inheritance. Although these alternate mechanisms of inheritance have shaken our blind faith in the central dogma, they whet our appetite for further revolutionary insights.

TorsinA and the torsinA-interacting protein printor have no impact on endoplasmic reticulum stress or protein trafficking in yeast.

Abstract: Early-onset torsion dystonia is a severe, life-long disease that leads to loss of motor control and involuntary muscle contractions. While the molecular etiology of the disease is not fully understood, a mutation in an AAA+ ATPase, torsinA, has been linked to disease onset. Previous work on torsinA has shown that it localizes to the endoplasmic reticulum, where there is evidence that it plays roles in protein trafficking, and potentially also protein folding. Given the high level of evolutionary conservation among proteins involved in these processes, the ability of human such proteins to function effectively in yeast, as well as the previous successes achieved in examining other proteins involved in complex human diseases in yeast, we hypothesized that Saccharomyces cerevisiae might represent a useful model system for studying torsinA function and the effects of its mutants. Since torsinA is proposed to function in protein homeostasis, we tested cells for their ability to respond to various stressors, using a fluorescent reporter to measure the unfolded protein response, as well as their rate of protein secretion. TorsinA did not impact these processes, even after co-expression of its recently identified interacting partner, printor. In light of these findings, we propose that yeast may lack an additional cofactor necessary for torsinA function or proteins required for essential post-translational modifications of torsinA. Alternatively, torsinA may not function in endoplasmic reticulum protein homeostasis. The strains and assays we describe may provide useful tools for identifying and investigating these possibilities and are freely available.

Yeast ectopically expressing abnormally processed proteins and uses therefor

Abstract: Disclosed are yeast ectopically expressing abnormally processed proteins and methods of screening to identify compounds that modulate the function of such abnormally processed proteins in yeast Compounds identified by such screens can be used to treat or prevent diseases associated with abnormally processed proteins or protein misfolding Such disease include Parkinson’s Disease, Parkinson’s Disease with accompanying dementia, Lewy body dementia, Alzheimer’s disease with Parkinsonism, and multiple system atrophy

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets.

Abstract: Proteins and their functional interactions form the backbone of the cellular machinery. Their connectivity network needs to be considered for the full understanding of biological phenomena, but the available information on protein-protein associations is incomplete and exhibits varying levels of annotation granularity and reliability. The STRING database aims to collect, score and integrate all publicly available sources of protein-protein interaction information, and to complement these with computational predictions. Its goal is to achieve a comprehensive and objective global network, including direct (physical) as well as indirect (functional) interactions. The latest version of STRING (11.0) more than doubles the number of organisms it covers, to 5090. The most important new feature is an option to upload entire, genome-wide datasets as input, allowing users to visualize subsets as interaction networks and to perform gene-set enrichment analysis on the entire input. For the enrichment analysis, STRING implements well-known classification systems such as Gene Ontology and KEGG, but also offers additional, new classification systems based on high-throughput text-mining as well as on a hierarchical clustering of the association network itself. The STRING resource is available online at https://string-db.org/.

Genome engineering using the CRISPR-Cas9 system

Abstract: Targeted nucleases are powerful tools for mediating genome alteration with high precision. The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate efficient genome engineering in eukaryotic cells by simply specifying a 20-nt targeting sequence within its guide RNA. Here we describe a set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified cell lines for downstream functional studies. To minimize off-target cleavage, we further describe a double-nicking strategy using the Cas9 nickase mutant with paired guide RNAs. This protocol provides experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency and analysis of off-target activity. Beginning with target design, gene modifications can be achieved within as little as 1-2 weeks, and modified clonal cell lines can be derived within 2-3 weeks.

A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3

Abstract: We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, upstream, downstream, splice site, or intergenic regions. Coding effects such as synonymous or non-synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frame shifts can be predicted. Here the use of SnpEff is illustrated by annotating ~356,660 candidate SNPs in ~117 Mb unique sequences, representing a substitution rate of ~1/305 nucleotides, between the Drosophila melanogaster w1118; iso-2; iso-3 strain and the reference y1; cn1 bw1 sp1 strain. We show that ~15,842 SNPs are synonymous and ~4,467 SNPs are non-synonymous (N/S ~0.28). The remaining SNPs are in other categories, such as stop codon gains (38 SNPs), stop codon losses (8 SNPs), and start codon gains (297 SNPs) in...

Principles of Neural Science

Abstract: I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or