Research Experience
HHMI at the University of California at Los Angeles
Structural Studies of Amyloid Oligomers and Amyloid Fibers
Postdoctoral Fellow/Staff Research Associate II with David Eisenberg, Ph.D.
University of California at Los Angeles
Structural Studies of Amyloid Oligomers and Amyloid Fibers
Postdoctoral Research Associate with Lin Chen, Ph.D.
University of Colorado at Boulder
Structural Studies of Transcription Factors Involved in Language and T-Cell Anergy
Graduate Student with Lin Chen, Ph.D.
University of Colorado at Boulder
Structural and Functional Studies of Rel Homology Region Containing Proteins
Research Assistant with John McCarrey, Ph.D.
Southwest Foundation For Biomedical Research, San Antonio, TX
Regulation of Transcription, DNA Methylation, and Chromatin Structure During Gametogenesis

Ph.D. Chemistry and Biochemistry University of Colorado at Boulder 2003
Lin Chen, Ph.D.
Structural and Functional Studies of Rel Homology Region Containing Proteins
M.A. Biochemistry and Molecular Biophysics Columbia University 1994
B.S. Molecular Biology University of Texas at Austin 1993

Research Interests
Mechanisms of Alzheimer's disease.
Protein misfolding and protein aggregation.
Combinatorial gene regulation.
Protein·DNA recognition.
Mechanisms of DNA repair.
DNA modification enzymes.

Published Research Articles
Number of citations is given in square brackets.
   See <>.
Reprints are author manuscripts. Published versions are available at the DOI links.
0 Stroud JC
The zipper groups of the amyloid state of proteins.
Acta Crystallogr Sect D-Biol Crystallogr 2013 Apr 69 4 540-5
9 Stroud JC Liu C Teng PK Eisenberg D
Toxic fibrillar oligomers of Amyloid-β have cross-β structure.
Proc Natl Acad Sci USA 2012 May 15 109 20 7717-22
Although amyloid fibers are found in neurodegenerative diseases, evidence points to soluble oligomers of amyloid-forming proteins as the cytotoxic species. Here, we establish that our preparation of toxic amyloid-β1-42 (Abeta42) fibrillar oligomers (TABFOs) shares with mature amyloid fibrils the cross-β structure, in which adjacent β-sheets adhere by interpenetration of protein side chains. We study the structure and properties of TABFOs by powder X-ray diffraction, EM, circular dichroism, FTIR spectroscopy, chromatography, conformational antibodies, and celluar toxicity. In TABFOs, Abeta42 molecules stack into short protofilaments consisting of pairs of helical β-sheets that wrap around each other to form a superhelix. Wrapping results in a hole along the superhelix axis, providing insight into how Abeta may form pathogenic amyloid pores. Our model is consistent with numerous properties of Abeta42 fibrillar oligomers, including heterogenous size, ability to seed new populations of fibrillar oligomers, and fiber-like morphology.
17 Bandukwala HS Wu Y Feuerer M Chen Y Barboza B Ghosh S Stroud JC Benoist C Mathis D Rao A Chen L
Structure of a Domain-Swapped FOXP3 Dimer on DNA and Its Function in Regulatory T Cells.
Immunity 2011 April 22 34 4 479-91
9 Stroud JC Oltman A Han A Bates DL Chen L
Structural basis of HIV-1 activation by NF-κB–a higher-order complex of p50:RelA bound to the HIV-1 LTR.
J Mol Biol 2009 Oct 16 393 1 98-112
The activation and latency of human immunodeficiency virus type 1 (HIV-1) are tightly controlled by the transcriptional activity of its long terminal repeat (LTR) region. The LTR is regulated by viral proteins as well as host factors, including the nuclear factor κB (NF-κB) that becomes activated in virus-infected cells. The two tandem NF-κB sites of the LTR are among the most highly conserved sequence elements of the HIV-1 genome. Puzzlingly, these sites are arranged in a manner that seems to preclude simultaneous binding of both sites by NF-κB, although previous biochemical work suggests otherwise. Here, we have determined the crystal structure of p50:RelA bound to the tandem κB element of the HIV-1 LTR as a dimeric dimer, providing direct structural evidence that NF-κB can occupy both sites simultaneously. The two p50:RelA dimers bind the adjacent κB sites and interact through a protein contact that is accommodated by DNA bending. The two dimers clamp DNA from opposite faces of the double helix and form a topological trap of the bound DNA. Consistent with these structural features, our biochemical analyses indicate that p50:RelA binds the HIV-1 LTR tandem κB sites with an apparent anti-cooperativity but enhanced kinetic stability. The slow on and off rates we observe may be relevant to viral latency because viral activation requires sustained NF-κB activation. Furthermore, our work demonstrates that the specific arrangement of the two κB sites on the HIV-1 LTR can modulate the assembly kinetics of the higher-order NF-κB complex on the viral promoter. This phenomenon is unlikely restricted to the HIV-1 LTR but probably represents a general mechanism for the function of composite DNA elements in transcription.
13 Bates DL Barthel KKB Wu Y Kalhor R Stroud JC Giffin MJ Chen L
Crystal structure of NFAT bound to the HIV-1 LTR tandem κB enhancer element.
Structure 2008 May 7 16 5 684-694
186 Dellisanti CD Yao Y Stroud JC Wang ZZ Chen L
Crystal structure of the extracellular domain of nACHR α1 bound to α-bungarotoxin at 1.94 Å resolution.
Nat Neurosci 2007 Aug 10 10 2 953-962
4 - Google Scholar Dellisanti CD Yao Y Stroud JC Wang ZZ Chen L
Structural determinants for α-neurotoxin sensitivity in muscle nAChR and their implications for the gating mechanism.
Channels (Austin) 2007 Jul-Aug 1 4 234-237
423 Wu Y Borde M Heissmeyer V Feuerer M Lapan AD Stroud JC Bates DL Guo L Han A Ziegler SF Mathis D Benoist C Chen L Rao A
FOXP3 controls regulatory T cell function through cooperation with NFAT.
Cell 2006 July 28 126 2 375-87
Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.
61 Stroud JC Wu Y Bates DL Han A Nowick K Paabo S Tong H Chen L
Structure of the forkhead domain of FOXP2 bound to DNA.
Structure 2006 Jan 14 1 159-66
FOXP (FOXP1-4) is a newly defined subfamily of the forkhead box (FOX) transcription factors. A mutation in the FOXP2 forkhead domain cosegregates with a severe speech disorder, whereas several mutations in the FOXP3 forkhead domain are linked to the IPEX syndrome in human and a similar autoimmune phenotype in mice. Here we report a 1.9 Å crystal structure of the forkhead domain of human FOXP2 bound to DNA. This structure allows us to revise the previously proposed DNA recognition mechanism and provide a unifying model of DNA binding for the FOX family of proteins. Our studies also reveal that the FOXP2 forkhead domain can form a domain-swapped dimer, made possible by a strategic substitution of a highly conserved proline in conventional FOX proteins with alanine in the P subfamily. Disease-causing mutations in FOXP2 and FOXP3 map either to the DNA binding surface or the domain-swapping dimer interface, functionally corroborating the crystal structure.
134 Lee T Hoofnagle AN Kabuyama Y Stroud J Min X Goldsmith EJ Chen L Resing KA Ahn NG
Docking motif interactions in MAP kinases revealed by hydrogen exchange mass spectrometry.
Mol Cell 2004 Apr 9 14 1 43-55
42 Han A Pan F Stroud JC Youn HD Liu JO Chen L
Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2.
Nature 2003 Apr 17 422 6933 730-4
20 Stroud JC Chen L
Structure of NFAT bound to DNA as a monomer.
J Mol Biol 2003 Dec 12 334 5 1009-22
53 Giffin MJ Stroud JC Bates D von Koenig KD Hardin J Chen L
Structure of NFAT1 bound as a dimer to the HIV-1 LTR κB element.
Nat Struct Biol 2003 Oct 10 10 800-6
64 Stroud JC Lopez-Rodriguez C Rao A Chen L
Structure of a TonEBP-DNA complex reveals DNA encircled by a transcription factor.
Nat Struct Biol 2002 Feb 9 2 90-4
27 Zhang LP Stroud J Eddy CA Walter CA McCarrey JR
Multiple elements influence transcriptional regulation from the human testis-specific PGK2 promoter in transgenic mice
Biol Reprod 1999 Jun 60 6 1329-37
23 Zhang LP Stroud JC Walter CA Adrian GS McCarrey JR
A gene-specific promoter in transgenic mice directs testis-specific demethylation prior to transcriptional activation In vivo.
Biol Reprod 1998 Aug 59 2 284-92
28 Kumari M Stroud JC Anji A McCarrey JR
Differential appearance of DNase I-hypersensitive sites correlates with differential transcription of Pgk genes during spermatogenesis in the mouse.
J Biol Chem 1996 Jun 14 271 24 14390-7

Manuscripts in Preparation
Stroud JC Liu C Eisenberg D
A wrapped model for amyloid-β fibers.
Kellman L Stroud JC
A recursive Bayesian estimation method for measuring kinetics of amyloid fibrillogenesis.

Book Chapters
Liu JO Chen L Pan F Stroud JC
Chapter 17: NFAT and MEF2, Two Families of Calcium-dependent Transcription Regulators
Gene Expression and Regulation Jun Ma Higher Education Press (Distributed by Springer Science and Business Media, LLC) Beijing P.R. China 2006
0387332081 | 978-0387332086 | 1

Honors and Awards
Ruth L. Kirschstein Postdoctoral Fellowship NIH 2007
Training Grant for Signal Transduction and Cell Cycle Regulation NIH 2000-2002
University Fellowship Recipient University of Colorado 1999
Graduate Fellowship Recipient Colorado Institute for Research in Biotechnology 1999
Presidential Scholar Incarnate Word College, San Antonio, TX 1988-1990

1998 Teaching Assistant General Chemistry 1 University of Colorado, Department of Chemistry and Biochemistry
1999 Teaching Assistant Introduction to Bioorganic Chemistry University of Colorado, Department of Chemistry and Biochemistry

Oral Presentations
Colorado Regional Transcription Meeting Denver, CO May 5, 2001 Talk Structural Basis of Combinatorial Gene Regulation in Eukaryotic Transcription
Rocky Mountain R-AXIS Users Meeting Boulder, CO May 19-20, 2001 Talk Crystallographic Analysis of the TonEBP/TonE Complex

Poster Presentations
Advanced Electron Microscopy in NanoMedicine Symposium UCLA, Los Angeles, CA Oct. 2-3, 2009 Poster Geometric Construct to Explain Amyloid Helicity
West Coast Protein Crystallography Workshop Asilomar, CA Apr. 5-8, 2009 Poster Using a Protein-DNA Complex to Template Protein Crystallization
West Coast Protein Crystallography Workshop Asilomar, CA Mar. 11-14, 2007 Poster YAMA: An Animation Engine for PyMOL
West Coast Protein Crystallography Workshop Asilomar, CA Mar. 20-23, 2005 Poster Fluorescence Studies of NFAT Support Crystallographic Observations
Keystone Symposia on NF-κB: From Bench to Bedside Keystone, CO Feb. 25-Mar. 3, 2002 Poster Structural Basis for Dimerization in the NFAT Family of Transcription Factors

Professional Service
Journal Reviews
Acta Crystallographica Section D
International Conference on Intelligent Systems for Molecular Biology
Journal of Cell Biology
Journal of Molecular Biology (co-reviewer with David Eisenberg)
Structure (co-reviewer with Lin Chen)
Grant Reviews
National Science Foundation, NSF 08557: Faculty Early Career Development (CAREER) Program

Selected Open Source Software
make-na Automation of making nucleic acids by NAB.
Over 2,100 uses per year.
fluorit Management and analysis of amyloid fluorimetric data.
pygmyplot A simplified plotting library based on matplotlib.
dssp2pdb Converts dssp output to pdb.
passerby A full featured password keeper.
Over 2,000 downloads.

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