个人简介

David Eisenberg is currently Professor of Chemistry and Biochemistry and Biological Chemistry, as well as HHMI Investigator. Before he came to UCLA, Eisenberg earned an A.B. in Biochemical Sciences from Harvard College and a D.Phil. from Oxford University in Theoretical Chemistry on a Rhodes Scholarship. After postdoctoral study at Princeton University on water and hydrogen bonding and at Caltech on protein crystallography, he joined the faculty at UCLA. Currently he studies protein interactions by X-ray crystallography, bioinformatics, and biochemistry, with an emphasis on amyloid-forming proteins. This recently recognized protein state offers opportunities to understand cells in health and disease, and in synthesizing new materials and in understanding processes as diverse as biofilms and corrosion. Eisenberg has published over 300 papers and reviews, holds half a dozen patents.

研究领域

Biochemistry/Biophysics/Structural and Computational Biology/Bioenergy and the Environment/Proteomics and Bioinformatics/Theory

David Eisenberg and his research group focus on protein interactions. In their experiments they study the structural basis for conversion of normal proteins to the amyloid state and conversion of prions to the infectious state. In bioinformatic work, they derive information on protein interactions from genomic and proteomic data, and design inhibitors of amyloid toxicity. Amyloid and prion diseases are diseases of protein aggregation in which a normal, functional protein converts to an abnormal, aggregated protein. The systemic amyloid diseases, such as dialysis-related amyloidosis, are apparently caused by the accumulation of fibers until organs fail. The neurodegenerative amyloid diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and the prion conditions, seem to be caused by smaller oligomers, intermediate in size between monomers and fibers. Our goals are to understand the general features of the conversion to the amyloid state, why some of the diseases are transmissible between organisms and others not, what the structures of the toxic units are, and how they exert their toxic actions, and how to interfere with amyloid toxicity.

近期论文

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Do TD, LaPointe NE, Sangwan S, Teplow DB, Feinstein SC, Sawaya MR, Eisenberg DS, Bowers MT (2014). Factors that drive Peptide assembly from native to amyloid structures: experimental and theoretical analysis of [leu-5]-enkephalin mutants. J Phys Chem B. Jul 3; 118(26):7247-56. Hochberg GK, Ecroyd H, Liu C, Cox D, Cascio D, Sawaya MR, Collier MP, Stroud J, Carver JA, Baldwin AJ, Robinson CV, Eisenberg DS, Benesch JL, Laganowsky A The structured core domain of αB-crystallin can prevent amyloid fibrillation and associated toxicity Proc Natl Acad Sci U S A. Apr 22; 111(16):E1562-70. Li D,Furukawa H, Deng H, Liu C, Yaghi OM, Eisenberg DS (2014). Designed amyloid fibers as materials for selective carbon dioxide capture. Proc. Natl. Acad. Sci. U.S.A. Jan 111(1):191-6. Ivanova MI, Sievers SA, Guenther EL, Johnson LM, Winkler DD, Galaleldeen A,Sawaya MR, Hart PJ, Eisenberg DS (2014). Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS. Proc. Natl. Acad. Sci. U.S.A. Jan 111(1):197-201. Goldschmidt L, Eisenberg D, Derewenda ZS (2014). Salvage or recovery of failed targets by mutagenesis to reduce surface entropy. Methods Mol. Biol. 1140:201-9. Kurt TD, Jiang L, Bett C, Eisenberg D, Sigurdson CJ (2014). A Proposed Mechanism for the Promotion of Prion Conversion Involving a Strictly Conserved Tyrosine Residue in the β2-α2 loop of PrPC. J. Biol. Chem. Apr 11;289(15):10660-7. Arbing MA, Chan S, Harris L, Kuo E, Zhou TT, Ahn CJ, Nguyen L, He Q, Lu J, Menchavez PT, Shin A, Holton T, Sawaya MR, Cascio D, Eisenberg D. Heterologous expression of mycobacterial Esx complexes in Escherichia coli for structural studies is facilitated by the use of maltose binding protein fusions. PLoS ONE. 8(11):e81753. Jiang L, Liu C, Leibly D, Landau M, Zhao M, Hughes MP, Eisenberg DS (2013). Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta. Elife. 2:e00857. Miallau L, Jain P, Arbing MA, Cascio D, Phan T, Ahn CJ, Chan S, Chernishof I, Maxson M, Chiang J, Jacobs WR, Eisenberg DS (2013). Comparative proteomics identifies the cell-associated lethality of M.tuberculosis RelBE-like toxin-antitoxin complexes. Structure.Apr 21(4):627-37. Stroud JC (2013) The zipper groups of the amyloid state of proteins. Acta Crystallogr. D Biol. Crystallogr. Apr 69(Pt 4):540-5. Sawaya MR, Cascio D, Eisenberg D (2013). Amyloid Structures at the Atomic Level: Insights from Crystallography In Amyloid Fibrils and Prefibrillar Aggregates: Molecular and Biological Properties. Editor: Daniel E. Otzen. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. [Book] Teng PK,Anderson NJ, Goldschmidt L, Sawaya MR, Sambashivan S, Eisenberg D (2012). Ribonuclease A suggests how proteins self-chaperone against amyloid fiber formation. Protein Sci. Jan. 21(1):26-37. Liu C, Zhao M, Jiang L, Cheng PN, Park J, Sawaya MR, Pensalfini A, Gou D, Berk AJ, Glabe CG, Nowick J, Eisenberg (2012). Out-of-register beta-sheets suggest a pathway to toxic amyloid aggregates Proc. Natl. Acad. Sci. U.S.A. Dec 109(51):20913-8. Cheng PN,Liu C, Zhao M, Eisenberg D, Nowick JS (2012). Amyloid beta-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity Nat Chem. Nov 4(11):927-33. Min AB, Miallau L, Sawaya MR, Habel J, Cascio D, Eisenberg D (2012). The crystal structure of the Rv0301-Rv0300 VapBC-3 toxin-antitoxin complex from M. tuberculosis reveals a Mg2+ ion in the active site and a putative RNA-binding site Protein Sci..Nov 21(11):1754-67. Gallat FX, Laganowsky A, Wood K, Gabel F, van Eijck L, Wuttke J, Moulin M, Härtlein M, Eisenberg D, Colletier JP, Zaccai G, Weik M (2012). Dynamical coupling of intrinsically disordered proteins and their hydration water: comparison with folded soluble and membrane proteins. Biophys. J. Jul 103(1):129-36. Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, Grishin NV, Frantz DE, Schneider JW, Chen S, Li L, Sawaya MR, Eisenberg D, Tycko R, McKnight SL (2012). Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell. May 149(4):753-67. Stroud JC, Liu C, Teng PK, Eisenberg D (2012). Toxic fibrillar oligomers of amyloid-beta have cross-beta structure Proc. Natl. Acad. Sci. U.S.A... May 109(20):7717-22. Eisenberg D, Jucker M (2012). The amyloid state of proteins in human diseases. Cell. Mar 148(6):1188-203. [Book] Laganowsky A, Liu C, Sawaya MR, Whitelegge JP, Park J, Zhao M, Pensalfini A,Soriaga AB, Landau M, Teng PK, Cascio D, Glabe C, Eisenberg D (2012). Atomic view of a toxic amyloid small oligomer. Science. Mar 335(6073):1228-31. Liu C,Sawaya MR, Eisenberg D (2011). Beta2-microglobulin forms three-dimensional domain-swapped amyloid fibrils with disulfide linkages. Nat. Struct. Mol. Biol. Jan 18(1):49-55. Colletier JP, Laganowsky A, Landau M, Zhao M, Soriaga AB, Goldschmidt L, Flot D, Cascio D, Sawaya MR, Eisenberg D. (2011). Molecular basis for amyloid-beta polymorphism. Proc. Natl. Acad. Sci. U.S.A... Oct 108(41):16938-43. Aranda B, Blankenburg H, Kerrien S, Brinkman FS, Ceol A, Chautard E, Dana JM, De Las Rivas J, Dumousseau M, Galeota E, Gaulton A, Goll J, Hancock RE, Isserlin R, Jimenez RC, Kerssemakers J, Khadake J, Lynn DJ, Michaut M, O'Kelly G, Ono K, Orchard S, Prieto C, Razick S, Rigina O, Salwinski L, Simonovic M, Velankar S, Winter A, Wu G, Bader GD, Cesareni G, Donaldson IM, Eisenberg D, Kleywegt GJ, Overington J, Ricard-Blum S, Tyers M, Albrecht M, Hermjakob H (2011). PSICQUIC and PSISCORE: accessing and scoring molecular interactions. Nat. Methods. Jul 8(7):528-9. Landau M, Sawaya MR, Faull KF, Laganowsky A, Jiang L, Sievers SA, Liu J, Barrio JR, Eisenberg D (2011). Towards a pharmacophore for amyloid. PLoS Biol. Jun 9(6):e1001080. Sievers SA, Karanicolas J, Chang HW, Zhao A, Jiang L, Zirafi O, Stevens JT, Munch J, Baker D, Eisenberg D (2011). Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature. Jul 475(7354):96-100. Liu C,Sawaya MR, Cheng PN, Zheng J, Nowick JS, Eisenberg D (2011). Characteristics of amyloid-related oligomers revealed by crystal structures of macrocyclic beta-sheet mimics J. Am. Chem. Soc. May 133(17):6736-44. Zhao M, Cascio D, Sawaya MR, Eisenberg D (2011). Structures of segments of alpha-synuclein fused to maltose-binding protein suggest intermediate states during amyloid formation Protein Sci... Jun 20(6):996-1004. Apostol MI, Wiltzius JJ, Sawaya MR, Cascio D, Eisenberg D (2011). Atomic structures suggest determinants of transmission barriers in mammalian prion disease. Biochemistry. Apr 50(13):2456-63. Zheng J, Liu C, Sawaya MR, Vadla B, Khan S, Woods RJ, Eisenberg D, Goux WJ, Nowick JS (2011). Macrocyclic beta-sheet peptides that inhibit the aggregation of a tau-protein-derived hexapeptide J. Am. Chem. Soc. Mar 133(9):3144-57. Chim N,Habel JE, Johnston JM, Krieger I, Miallau L, Sankaranarayanan R, Morse RP, Bruning J, Swanson S, Kim H, Kim CY, Li H, Bulloch EM, Payne RJ, Manos-Turvey A, Hung LW, Baker EN, Lott JS, James MN, Terwilliger TC, Eisenberg DS, Sacchettini JC, Goulding CW (2011). The TB Structural Genomics Consortium: a decade of progress. Tuberculosis (Edinb). Mar 91(2):155-72. [Book] Khakshoor O, Lin AJ, Korman TP, Sawaya MR, Tsai SC, Eisenberg D, Nowick JS. (2010). X-ray crystallographic structure of an artificial beta-sheet dimer. J Am Chem Soc.. Aug 2010. 25;132(33): 11622-8 [Abstract] Goldschmidt L, Teng PK, Riek R, Eisenberg D. (2010). Identifying the amylome, proteins capable of forming amyloid-like fibrils.Proc. Natl. Acad. Sci. U.S.A.. Feb 2010. 107(8):3487-92. [Abstract] The amylome is the universe of proteins that are capable of forming amyloid-like fibrils. Here we investigate the factors that enable a protein to belong to the amylome. A major factor is the presence in the protein of a segment that can form a tightly complementary interface with an identical segment, which permits the formation of a steric zipper-two self-complementary beta sheets that form the spine of an amyloid fibril. Another factor is sufficient conformational freedom of the self-complementary segment to interact with other molecules. Using RNase A as a model system, we validate our fibrillogenic predictions by the 3D profile method based on the crystal structure of NNQQNY and demonstrate that a specific residue order is required for fiber formation. Our genome-wide analysis revealed that self-complementary segments are found in almost all proteins, yet not all proteins form amyloids. The implication is that chaperoning effects have evolved to constrain self-complementary segments from interaction with each other. Laganowsky A, Benesch JL, Landau M, Ding L, Sawaya MR, Cascio D, Huang Q, Robinson CV, Horwitz J, Eisenberg D. (2010). Crystal structures of truncated alphaA and alphaB crystallins reveal structural mechanisms of polydispersity important for eye lens function.Protein Sci.. May 2010. 19(5):1031-43. [Abstract] Small heat shock proteins alphaA and alphaB crystallin form highly polydisperse oligomers that frustrate protein aggregation, crystallization, and amyloid formation. Here, we present the crystal structures of truncated forms of bovine alphaA crystallin (AAC(59-163)) and human alphaB crystallin (ABC(68-162)), both containing the C-terminal extension that functions in chaperone action and oligomeric assembly. In both structures, the C-terminal extensions swap into neighboring molecules, creating runaway domain swaps. This interface, termed DS, enables crystallin polydispersity because the C-terminal extension is palindromic and thereby allows the formation of equivalent residue interactions in both directions. That is, we observe that the extension binds in opposite directions at the DS interfaces of AAC(59-163) and ABC(68-162). A second dimeric interface, termed AP, also enables polydispersity by forming an antiparallel beta sheet with three distinct registration shifts. These two polymorphic interfaces enforce polydispersity of alpha crystallin. This evolved polydispersity suggests molecular mechanisms for chaperone action and for prevention of crystallization, both necessary for transparency of eye lenses. Wang L, Schubert D, Sawaya MR, Eisenberg D, Riek R. (2010). Multidimensional structure-activity relationship of a protein in its aggregated states.Angew. Chem. Int. Ed. Engl.. May 2010. 49(23):3904-8. [Abstract] Khakshoor O, Lin AJ, Korman TP, Sawaya MR, Tsai SC, Eisenberg D, Nowick JS. (2010). X-ray crystallographic structure of an artificial beta-sheet dimer.J. Am. Chem. Soc.. Aug 2010. 132(33):11622-8. [Abstract] Apostol MI, Sawaya MR, Cascio D, Eisenberg D. (2010). Crystallographic studies of prion protein (PrP) segments suggest how structural changes encoded by polymorphism at residue 129 modulate susceptibility to human prion disease.J. Biol. Chem.. Sep 2010. 285(39):29671-5. [Abstract] A single nucleotide polymorphism (SNP) in codon 129 of the human prion gene, leading to a change from methionine to valine at residue 129 of prion protein (PrP), has been shown to be a determinant in the susceptibility to prion disease. However, the molecular basis of this effect remains unexplained. In the current study, we determined crystal structures of prion segments having either Met or Val at residue 129. These 6-residue segments of PrP centered on residue 129 are "steric zippers," pairs of interacting β-sheets. Both structures of these "homozygous steric zippers" reveal direct intermolecular interactions between Met or Val in one sheet and the identical residue in the mating sheet. These two structures, plus a structure-based model of the heterozygous Met-Val steric zipper, suggest an explanation for the previously observed effects of this locus on prion disease susceptibility and progression. Arbing MA, Kaufmann M, Phan T, Chan S, Cascio D, Eisenberg D. (2010). The crystal structure of the Mycobacterium tuberculosis Rv3019c-Rv3020c ESX complex reveals a domain-swapped heterotetramer.Protein Sci.. Sep 2010. 19(9):1692-703. [Abstract] Mycobacterium tuberculosis encodes five gene clusters (ESX-1 to ESX-5) for Type VII protein secretion systems that are implicated in mycobacterial pathogenicity. Substrates for the secretion apparatus are encoded within the gene clusters and in additional loci that lack the components of the secretion apparatus. The best characterized substrates are the ESX complexes, 1:1 heterodimers of ESAT-6 and CFP-10, the prototypical member that has been shown to be essential for Mycobacterium tuberculosis pathogenesis. We have determined the structure of EsxRS, a homolog of EsxGH of the ESX-3 gene cluster, at 1.91 Å resolution. The EsxRS structure is composed of two four-helix bundles resulting from the 3D domain swapping of the C-terminal domain of EsxS, the CFP-10 homolog. The four-helix bundles at the extremities of the complex have a similar architecture to the structure of ESAT-6·CFP-10 (EsxAB) of ESX-1, but in EsxRS a hinge loop linking the α-helical domains of EsxS undergoes a loop-to-helix transition that creates the domain swapped EsxRS tetramer. Based on the atomic structure of EsxRS and existing biochemical data on ESX complexes, we propose that higher order ESX oligomers may increase avidity of ESX binding to host receptor molecules or, alternatively, the conformational change that creates the domain swapped structure may be the basis of ESX complex dissociation that would free ESAT-6 to exert a cytotoxic effect. Laganowsky A, Eisenberg D. (2010). Non-3D domain swapped crystal structure of truncated zebrafish alphaA crystallin.Protein Sci.. Oct 2010. 19(10):1978-84. [Abstract] In previous work on truncated alpha crystallins (Laganowsky et al., Protein Sci 2010; 19:1031-1043), we determined crystal structures of the alpha crystallin core, a seven beta-stranded immunoglobulin-like domain, with its conserved C-terminal extension. These extensions swap into neighboring cores forming oligomeric assemblies. The extension is palindromic in sequence, binding in either of two directions. Here, we report the crystal structure of a truncated alphaA crystallin (AAC) from zebrafish (Danio rerio) revealing C-terminal extensions in a non three-dimensional (3D) domain swapped, "closed" state. The extension is quasi-palindromic, bound within its own zebrafish core domain, lying in the opposite direction to that of bovine AAC, which is bound within an adjacent core domain (Laganowsky et al., Protein Sci 2010; 19:1031-1043). Our findings establish that the C-terminal extension of alpha crystallin proteins can be either 3D domain swapped or non-3D domain swapped. This duality provides another molecular mechanism for alpha crystallin proteins to maintain the polydispersity that is crucial for eye lens transparency.