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BIOLOGICAL SCIENCES / BIOCHEMISTRY
Molecular basis for passive immunotherapy of Alzheimer's disease
*Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996; Graduate School of Medicine, University of Tennessee, Knoxville, TN 37920; Division of Biology, California Institute of Technology, Pasadena, CA 91125; HSC Core Research Facilities, University of Utah, Salt Lake City, UT 84132; ¶Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; and ||Department of Pharmacology, Case School of Medicine, Cleveland, OH 44106
Edited by David R. Davies, National Institutes of Health, Bethesda, MD, and approved August 15, 2007 (received for review June 22, 2007)
Amyloid aggregates of the amyloid-
(A) peptide are implicated in the pathology of Alzheimer's disease. Anti-A monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-A mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize A monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the A(1–8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIP1 is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to A(1–8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target A with improved specificity and higher affinity.
amyloid | crystal structure | EFRH | monoclonal antibody | EFRHD
Author contributions: R.W., D.G.M., and C.D. designed research; A.S.G., L.T.D., S.O., R.L.R., E.H., J.K., and C.D. performed research; A.S.G., L.T.D., S.O., R.L.R., J.K., R.W., D.G.M., and C.D. analyzed data; and A.S.G., R.W., P.H.P., and C.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 2IPT, 2IPU, 2IQ9, 2IQA, 2ROZ, and 2ROW).
This article contains supporting information online at www.pnas.org/cgi/content/full/0705888104/DC1.
**To whom correspondence should be addressed at: Case School of Medicine, 10900 Euclid Avenue, BRB, Room 926, Cleveland, OH 44106-4965. E-mail: chris.dealwis{at}case.edu
© 2007 by The National Academy of Sciences of the USA
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