FIRST CLOSE-UP OF AMYLOID FIBRILS
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PROTEIN STRUCTURE FIRST CLOSE-UP OF AMYLOID FIBRILS Steric zipper appears to be key structure in disease-associated protein aggregates T HE FIRST DETAILED ATOM- IC view of amyloid fibrils in- dicates that pairs of tightly interdigitating β-sheets are a com- mon structural feature in these misfolded protein aggregates. Amyloid fibrils are associated with some 20 diseases, ranging from Alzheimer's and type 2 di- abetes to prion diseases. The new structure could aid the search for therapeutic agents that can im- pede formation or accelerate breakdown of amyloid in these conditions. Amyloid fibrils formed from different proteins are known to have common structural proper- ties, such as a "cross-β spine," a set of protein β-strands that run perpendicular to each fibril's long axis. An atomic model of such fi- brils has not been available until now, however, primarily because of the difficulty in creating amy- loid crystals large enough to be analyzed by X-ray crystallography "For more than 30 years, sci- entists have wondered what the molecular-level details are of the cross-β structure," says Howard Hughes Medical Institute inves- tigator David Eisenberg of the University of California, Los An- geles, who led the group that car- ried out the new study (Nature 2005, 435, ITS). "We have been fortunate to see the answer." The work shows that a six- or seven-residue protein segment "can bind to other copies of itself to form two tightly interdigitat- ing β-sheets," Eisenberg explains. "We call this tight interdigitation a 'steric zipper.'As the two sheets zip up, water is excluded, giving a dry, stable interface that is hard to reopen."The structure differs considerably from other known β-sheet architectures, and the zipper feature helps explain why amyloid fibrils are as stable and persistent as they are. To solve the structure, Eisen- berg and coworkers laboriously grew tiny crystals of amyloid fi- brils—about l/50,000th the size of conventional protein crystals, at best. They then used special techniques for structural analysis of very small crystals developed by crystallographer Christian Riekel and coworkers at the Eu- ropean Synchrotron Radiation Facility, Grenoble, France. In a Nature commentary, pro- fessor of chemical and structural biology Christopher M. Dobson of Cambridge University calls the study "a breakthrough." And pro- fessor of cellular and molecular pharmacologyJonathan S. Weiss- man of the University of Califor- nia, San Francisco, says determin- ZIP IT In amyloid fibril structure, polar side chains on antiparallel pairs of β-strands interdigitate across the nearly water-free interface between the two sheets. Shapes of the side chains complement each other closely and look like the teeth of a zipper when seen from above (right). Center arrow indicates long axis of amyloid fibril, and red plus signs are water molecules. ing the structure "is a monumental achievement that will open up a new era in the structural analysis of amyloids."—STU BORMAN WELCH AWARD Harvard Chemistry Professor Honored For Long, Diverse Career G eorge M. Whitesides, the Mallinckrodt Professor of Chemistry at Harvard University, will receive the 2005 Welch Award in Chem- istry in honor of "more than four decades of life-enhancing contributions to diverse areas of chemistry." The $300,000 award has been given annually by the Houston-based Welch Foundation since 1972. Whitesides has worked in many areas of chemistry, par- ticularly physical organic chemistry, biochemistry, sur- face science, and materials science. His many contribu- tions to surface science in- clude work in self-assembled monolayers and the develop- Whitesides ment of soft lithog- raphy. He also pioneered meso- scale self-assem- bly, in which com- ponents on the millimeter or cen- timeter scale spon- taneously organize themselves into larger structures. "Identifying interesting prob- lems, learning how things work, and applying those in- sights to benefit people has been extremely fulfilling, and I am honored that the Welch Foundation has recognized me for such work," Whitesides says. "I share the foundation's dedication to basic research in chemistry and look forward to continuing my work in exciting new directions that continually expand chemistry's borders." Whitesides re- ceived an A.B. from Harvard in 1960 and a Ph.D. from Califor- nia Institute of Tech- nology in 1964. He served on the faculty at Massachusetts Institute of Technology from 1963 to 1982, when he joined the faculty at Harvard. White- sides' many awards include the National Medal of Science, the ACS Award in Pure Chem- istry, and the Arthur C. Cope Award.—CELIA HENRY WWW.CEN-ONLIN E.ORG C& EN / JU^ 13, 2005 NEWS OF THE WEEK ce "=t Σ ο ce u_ Q Q. < Q <
Transcript of FIRST CLOSE-UP OF AMYLOID FIBRILS
P R O T E I N S T R U C T U R E
FIRST CLOSE-UP OF AMYLOID FIBRILS Steric zipper appears to be key structure in disease-associated protein aggregates
THE FIRST DETAILED ATOMIC view of amyloid fibrils indicates that pairs of tightly
interdigitating β-sheets are a common structural feature in these misfolded protein aggregates.
Amyloid fibrils are associated with some 2 0 diseases, ranging from Alzheimer's and type 2 diabetes to prion diseases. T h e new structure could aid the search for therapeutic agents that can imp e d e fo rma t ion or acce le ra te breakdown of amyloid in these conditions.
Amyloid fibrils formed from different proteins are known to have common structural properties, such as a "cross-β spine," a set of protein β-strands that run perpendicular to each fibril's long axis. An atomic model of such fibrils has not been available until now, however, primarily because of the difficulty in creating amyloid crystals large enough to be analyzed by X-ray crystallography
"For more than 30 years, scientists have wondered what the molecular-level details are of the cross-β structure," says Howard Hughes Medical Institute investigator David Eisenberg of the University of California, Los Angeles, who led the group that carried out the new study (Nature 2 0 0 5 , 435, ITS). "We have been fortunate to see the answer."
The work shows that a six- or seven-residue prote in segment "can bind to other copies of itself to form two tightly interdigitating β-sheets," Eisenberg explains. "We call this tight interdigitation a 'steric zipper.'As the two sheets zip up, water is excluded, giving a dry, stable interface that is hard to reopen."The structure differs
considerably from other known β-sheet archi tectures , and the zipper feature helps explain why amyloid fibrils are as stable and persistent as they are.
To solve the structure, Eisenberg and coworkers laboriously grew tiny crystals of amyloid fibrils—about l /50 ,000th the size of conventional protein crystals, at best. They then used special techniques for structural analysis of very small crystals developed by crys ta l lographer Chr i s t i an Riekel and coworkers at the European Synchrotron Radiat ion Facility, Grenoble, France.
In a Nature commentary, professor of chemical and structural biology Christopher M. Dobson
of Cambridge University calls the study "a breakthrough." And professor of cellular and molecular pharmacology Jonathan S. Weiss-man of the University of California, San Francisco, says determin-
ZIP IT In amyloid fibril structure, polar side chains on antiparallel pairs of β-strands interdigitate across the nearly water-free interface between the two sheets. Shapes of the side chains complement each other closely and look like the teeth of a zipper when seen from above (right). Center arrow indicates long axis of amyloid fibril, and red plus signs are water molecules.
ing the structure "is a monumental achievement that will open up a new era in the structural analysis of amyloids."—STU BORMAN
W E L C H A W A R D
Harvard Chemistry Professor Honored For Long, Diverse Career
George M. Whitesides, the Mallinckrodt Professor of Chemistry at Harvard
University, will receive the 2005 Welch Award in Chemistry in honor of "more than four decades of life-enhancing contributions to diverse areas of chemistry." The $300,000 award has been given annually by the Houston-based Welch Foundation since 1972.
Whitesides has worked in many areas of chemistry, particularly physical organic chemistry, biochemistry, surface science, and materials science. His many contributions to surface science include work in self-assembled monolayers and the develop-
Whitesides
ment of soft lithography. He also pioneered meso-scale self-assembly, in which components on the millimeter or centimeter scale spontaneously organize themselves into larger structures.
"Identifying interesting problems, learning how things work, and applying those insights to benefit people has been extremely fulfilling, and I am honored that the Welch Foundation has recognized me for such work," Whitesides says. "I share the foundation's dedication to basic research in
chemistry and look forward to continuing my work in exciting new directions that continually expand chemistry's borders."
Whitesides received an A.B. from Harvard in 1960 and a Ph.D. from Califor-nia Institute of Tech
nology in 1964. He served on the faculty at Massachusetts Institute of Technology from 1963 to 1982, when he joined the faculty at Harvard. White-sides' many awards include the National Medal of Science, the ACS Award in Pure Chemistry, and the Arthur C. Cope Award.—CELIA HENRY
W W W . C E N - O N L I N E.ORG C& EN / JU^ 13, 2005
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