Susan Lindquist, Ph.D.
Department of Biology
Member, Whitehead Institute for Biomedical Research
Professor, Biology Department
Ph.D. Biology, 1976 Harvard University
Postdoctoral Fellow, 1976-1978 The University of Chicago
The intracellular environment is highly concentrated and dynamic. The goals of the Lindquist Lab are to identify cellular mechanisms that ensure accurate protein folding in this complex environment, to investigate the consequences of protein misfolding, and to understand how these contribute to processes as diverse as evolution and human disease.
Our lab has uncovered new paradigms for evolution involving Hsp90, a protein that chaperones the correct folding of other proteins, and Sup35, a translation termination factor that can exist in a prion conformation where function is lost. By completely different mechanisms, these proteins promote the storage and release of previously hidden genetic variation, producing an astounding diversity of new phenotypes. Hsp90's chaperone role provides a long sought-after explanation of how evolution might proceed more rapidly in times of environmental stress, and a potential mechanism for the evolution of transformed cells within an organism. To identify comprehensively the nature of the genetic variation and specify its effects upon function in such a large network necessitates a systems approach, including developing new methods for high throughput screening and integration of results from thousands of experiments. The natural genetic diversity present among isolates of model organisms such as yeast augurs a rich resource for revealing complexities in molecular pathways and exploring the selective pressures that shaped them and affected the evolution of whole genomes.
In complementary studies we have focused on predicting and experimentally determining the structure of Sup35 in its prion form and the mechanisms by which Sup35 aggregates into amyloid. We have applied simultaneous optical trapping and fluorescence to the study of these amyloid fibrils, revealing completely unexpected properties. Individual subdomains of Sup35 prion fibrils can unfold and extend fibril length without disrupting fibril integrity. This finding could explain the astonishing structural integrity of functional amyloids such as biofilms.
As amyloid proteins play an important role in devastating neurodegenerative diseases, this information will also be extremely beneficial for neurodegenerative disease research. Many such diseases, including Parkinson’s and Alzheimer’s, are associated with protein misfolding. Studying the molecular mechanism of toxicity associated with these diseases in yeast provides major advantages: ease of manipulation, short generation time, and a huge number of genetic tools available. We have created yeast models of complex diseases that reproduce the cellular toxicity characteristics of these diseases, and we have profiled these models with transcriptional microarrays and high-throughput genetic screening. To analyze and integrate complex data sets generated with our yeast models, we developed ResponseNet, a computational approach that uses flow algorithms to bridge the gap between genetic and transcriptional data by known molecular interactions.
The common challenges for investigating these phenomena are to develop high-throughput assays, to create sophisticated methods for efficiently analyzing the large data output, and to synthesize new experimental results with the wealth of information in the literature and public databases. The interdisciplinary CSBi approach provides the ideal environment to bring together engineers, information scientists, biomathematicians, biocomputing experts and biologists to create the tools necessary to meet these challenges.
- Jarosz DF, Lindquist S, 2010. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330: 1820-4.
- Dong J, Castro CE, Boyce MC, Lang MJ, Lindquist S, 2010. Optical Trapping with High Forces Reveals Unexpected Behaviors of Prion Fibrils. Nat Struct Mol Biol 17: 1422-30.
- Alberti S, Halfmann R, King O, Kapila A, Lindquist S, 2009. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137: 146-158.
- Bryan, AW, Menke M, Cowen LJ, Lindquist S, Berger B, 2009. BETASCAN: Probable β−amyloids identified by pairwise probabilistic analysis. PLoS Comp Biol 5: e1000333.
- Yeger-Lotem E, Riva L, Su LJ, Gitler AD, Cashikar A, King OD, Auluck PK, Geddie ML, Valastyan JS, Karger DR, Lindquist S, Fraenkel E, 2009. Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity. Nat Genet 41: 316-23
- Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet J-C, Lindquist S, 2009. α-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 41: 308-15.
- Krishnan R, Lindquist SL, 2005. Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature 435:765-72.
- True H, Berlin I Lindquist S, 2004. Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. Nature 431: 184-87.
Last Updated: January 20, 2011