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:~/ rthur M. Sackler C O L L O Q U I A OF THE NATIONAL ACADEMY OF SCIENCES Self-Perpetuating Structural States in Biology, Disease, and Genetics Eclitecl by Susan Linguist and Steve Henikoff

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1 Ill Cover photograph: Ribbon diagram of the protein structural interface associated with the disease amyloidogenic protein transthyretin. The side chains of naturally occurring mutations, which influence the age and severity of disease onset, are shown in white. These mutations alter the energy landscape of the partially unfolded protein. This in turn can either exacerbate or prevent disease. Image courtesy of Ted Foss. See article by Hammarstrom et al. on pages 16427-16432. This work is reprinted from the Proceedings of the National Academy of Sciences of the United States of America, vol. 99, suppl. 4, pp. 16377-16506, December 10, 2002, and includes articles from the Arthur M. Sackler Colloquium on Self-Perpetuating Structural States in Biology, Disease, and Genetics, held at the National Academy of Sciences in Washington, DC, March 22-24, 2002. The articles appearing in these pages were contributed by speakers at the colloquium and were anonymously reviewed, but they have not been independently reviewed by the Academy. Any opinions, findings, conclusions, or recommendations expressed in this work are those of the authors and do not necessarily reflect the views of the National Academy of Sciences. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the U.S. Congress in 1863, the Academy has a mandate that requires it to advise the Federal Government on scientific and technical matters. ISBN: 309-08445-8. (3 Copyright by the National Academy of Sciences, USA All rights reserved. Published 2002 Printed in the United States of America

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<_Arthur M. Sack/er _ C O L L O Q U I A ~~ OF THE NATIONAL ACADEMY OF SCIENCES Self-Perpetuating Structural States in Biology, Disease, and Genetics National Academy of Sciences Washington, D.C.

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Arthur M. Sackler, M.D. 1 91 3-1 987 Born in Brooklyn, New York, Arthur M. Sackler was edu- cated in the arts, sciences, and humanities at New York University. These interests remained the focus of his life, as he became widely known as a scientist, art collector, and philan- thropist, endowing institutions of learning and culture through- out the world. He felt that his fundamental role was as a doctor, a vocation he decided upon at the age of four. After completing his internship and service as house physician at Lincoln Hospital in New York City, he became a resident in psychiatry at Creed- moor State Hospital. There, in the 1940s, he started research that resulted in more than 150 papers in neuroendocrinology, psychiatry, and experimental medicine. He considered his scientific research in the metabolic basis of schizophrenia his most significant contribution to science and served as editor of the Journal of Clinical and Experimental Psychobiology from 1950 to 1962. In 1960 he started publication of Medical Tribune, a weekly medical newspaper that reached over one million readers in 20 countries. He established the Laboratories for Therapeutic Research in 1938, a facility in New York for basic research that he directed until 1983. As a generous benefactor to the causes of medicine and basic science, Arthur Sackler built and contributed to a wide range of scientific institutions: the Sackler School of Medicine established in 1972 at Tel Aviv University, Tel Aviv, Israel; the Sackler Institute of Graduate Biomedical Science at New York University, founded in 1980; the Arthur M. Sackler Science Center dedicated in 1985 at Clark University, Worcester, Massachusetts; and the Sackler School of Graduate Biomedical Sciences, established in 1980, and the Arthur M. Sackler Center for Health Communications, established in 1986, both at Tufts University, Boston, Massachusetts. His pre-eminence in the art world is already legendary. According to his wife Jillian, one of his favorite relaxations was to visit museums and art galleries and pick out great pieces others had overlooked. His interest in art is reflected in his philanthropy; he endowed galleries at the Metropolitan Museum of Art and Princeton University, a museum at Harvard University, and the Arthur M. Sackler Gallery of Asian Art in Washington, DC. True to his oft-stated determination to create bridges between peoples, he offered to build a teaching museum in China, which Jillian made possible after his death, and in 1993 opened the Arthur M. Sackler Museum of Art and Archaeology at Peking University in Beijing. In a world that often sees science and art as two separate cultures, Arthur Sackler saw them as inextricably related. In a speech given at the State University of New York at Stony Brook, Some rejections on the arts, sciences and humanities, a year before his death, he observed: "Communication is, for me, theprimum movens of all culture. In the arts. . . I find the emotional component most moving. In science, it is the intellectual content. Both are deeply interlinked in the humanities." The Arthur M. Sackler Colloquia at the National Academy of Sciences pay tribute to this faith in communication as the prime mover of knowledge and culture.

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PNAS Proceedings of the National Academy of Sciences of the United States of America Contents Papers from the Arthur M. Sackler Colloquium of the National Academy of Sciences INTRODUCTION 16377 Self-perpetuating structural states in biology, disease, and genetics Susan L. Lindquist and Steven Henikoff COLLOQUIUM PAPERS 16378 Transmission of prions C. Weissmann, M. Enari, P.-C. Klohn, D. Rossi, and E. Flechsig 16384 Conservation of a portion of the S. cerevisiae Ure2p prion domain that interacts with the full-length protein Herman K. Edskes and Reed B. Wickner 16392 Interactions among prions and prion "strains" in yeast Michael E. Bradley, Herman K. Edskes, Joo Y. Hong, Reed B. Wickner, and Susan W. Liebman 16400 Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay Volker Heiser, Sabine Engemann, Wolfgang Brocker, Ilona Dunkel, Annett Boeddrich, Stephanie Waelter, Eddi Nordhoff, Rudi Lurz, Nancy Schugardt, Susanne Rautenberg, Christian Herhaus, Gerhard Barnickel, Henning Bottcher, Hans Lehrach, and Erich E. Wanker 16407 Chaperoning brain degeneration Nancy M. Bonini 16412 Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity Hideki Sakahira, Peter Breuer, Manajit K. Hayer-Hartl, and F. Ulrich Hartl 16419 Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases Fabrizio Chiti, Martino Calamai, Niccolo Taddei, Massimo Stefani, Giampietro Ramponi, and Christopher M. Dobson 16427 Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity Per Hammarstrom, Xin Jiang, Amy R. Hurshman, Evan T. Powers, and Jeffe~y W. Kelly 16433 The insulation of genes from external enhancers and silencing chromatin Bonnie Burgess-Beusse, Catherine Farrell, Miklos Gaszner, Michael Litt, Vesco Mutskov, Felix Recillas-Targa, Melanie Simpson, Adam West, and Ga~y Felsenfeld 16438 Histone H3 Iysine 4 methylation is mediated by Set1 and promotes maintenance of active chromatin states in fission yeast Ken-ichi Noma and Shiv I. S. Grewal 16446 Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion lPSI+] Jia-Jia Liu, Neal Sondheimer, and Susan L. Lindquist 16454 Heritable chromatin structure: Mapping "memory" in histones H3 and H4 Christine M. Smith, Zara W. Haimberger, Catherine 0. Johnson, Alex J. Wolf, Philip R. Gafken, Zhongli Zhang, Mark R. Parthun, and Daniel E. Gottschling 16462 Does heterochromatin protein 1 always follow code? Yuhong Li, Dawn A. Kirschmann, and Lori L. Wallrath 16470 Self-perpetuating epigenetic pill switches in bacteria Aaron Hernday, Margareta Krabbe, Bruce Braaten, and David Low 16477 Histone H3 variants specify modes of chromatin assembly Kami Ahmad and Steven Henikoff 16485 Induction and maintenance of nonsymmetrical DNA methylation in Neurospora Eric U. Selker, Michael Freitag, GregoIy 0. Kothe, Brian S. Margolin, Michael R. Rountree, C. David Allis, and Hisashi Tamaru 16491 Locus-specific control of asymmetric and CpNpG methylation by the DRM and CMT3 methyltransferase genes Xiaofeng Cao and Steven E. Jacobsen 16499 RNA-directed DNA methylation in Arabidopsis Werner Aufsatz, M. Florian Mette, Johannes van der Winden, Antonius J. M. Matzke, and Marjori Matzke

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