Daniel Southworth, PhD
Professor
Institute for Neurodegenerative Diseases
School of Medicine

Awards

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• Top Scientist Development Award, American Heart Association, 2013-2016
• New Investigator Award, Alzheimer's Association, 2012-2014
• Biological Sciences Scholar, University of Michigan, 2011
• Postdoctoral Fellowship, American Cancer Society, 2007-2010
• Paul Ehrlich Research Award, Johns Hopkins University, 2004

Websites

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• Southworth Lab (southworthlab.ucsf.edu)
• Posts on X SouthworthLab (X.com)

Videos

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• Hsp104 Disaggregation in Action (youtube.com)

Grants and Projects

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• Mechanisms of Protein Disaggregation and Turnover by AAA+ Chaperones, NIH, 2021-2025
• Probing the Role of Chaperone-TPR Complexes in Tau Proteostasis, NIH, 2020-2024
• Mechanisms of motor neuron toxicity in Kennedy disease, NIH, 2007-2022
• The molecular mechanisms of nutrient- and stress-dependent mTORC1 regulation mediated by human Sestrin2., NIH, 2016-2021
• Defining the conformational cycle of nitric oxide synthases, NIH, 2015-2021
• Mechanisms of Activation for Human Small Heat Shock Proteins: An Integrated Approach, NIH, 2006-2020
• Exploration of Molecular Chaperone Complexes During Active Protein Triage, NIH, 2014-2019

Publications (81)

Top publication keywords:
Valosin Containing ProteinTacrolimus Binding ProteinsMolecular ChaperonesCaseinsEndopeptidase ClpHeat-Shock ProteinsCryoelectron Microscopytau ProteinsChaperonin 60Saccharomyces cerevisiae ProteinsProtein FoldingModels, MolecularAdenosine TriphosphateHSP90 Heat-Shock ProteinsEscherichia coli Proteins

• Recombinant Antibodies Inhibit Enzymatic Activity of the E3 Ubiquitin Ligase CHIP via Multiple Mechanisms.
  The Journal of biological chemistry 2025 Chung DH, Connelly EJ, Unnikrishnan A, Chuo SW, Wucherer K, Nadel CM, Gestwicki JE, Southworth DR, Craik CS
• Design principles to tailor Hsp104 therapeutics.
  Cell reports 2024 Lin J, Carman PJ, Gambogi CW, Kendsersky NM, Chuang E, Gates SN, Yokom AL, Rizo AN, Southworth DR, Shorter J
• Interactions with regulatory antibodies modulate CHIP E3 ubiquitin ligase-driven tau clearance.
  Alzheimer's & Dementia 2024 Aparna Unnikrishnan, Emily J Connelly, Dong hee Chung, Cory M Nadel, Aye Thwin, Charles S Craik, Daniel Southworth
• Cryo-EM structure of a novel α-synuclein filament subtype from multiple system atrophy.
  FEBS letters 2024 Yan NL, Candido F, Tse E, Melo AA, Prusiner SB, Mordes DA, Southworth DR, Paras NA, Merz GE
• CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.
  bioRxiv : the preprint server for biology 2024 Samelson AJ, Ariqat N, McKetney J, Rohanitazangi G, Bravo CP, Bose R, Travaglini KJ, Lam VL, Goodness D, Dixon G, Marzette E, Jin J, Tian R, Tse E, Abskharon R, Pan H, Carroll EC, Lawrence RE, …

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• Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils.
  PLoS biology 2024 Huettemann P, Mahadevan P, Lempart J, Tse E, Dehury B, Edwards BFP, Southworth DR, Sahoo BR, Jakob U
• Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP.
  Nature communications 2024 Nadel CM, Pokhrel S, Wucherer K, Oehler A, Thwin AC, Basu K, Callahan MD, Southworth DR, Mordes DA, Craik CS, Gestwicki JE
• Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly.
  Nature structural & molecular biology 2024 Braxton JR, Shao H, Tse E, Gestwicki JE, Southworth DR
• Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer's disease fold.
  Acta neuropathologica communications 2024 Ghosh U, Tse E, Yang H, Shi M, Caro CD, Wang F, Merz GE, Prusiner SB, Southworth DR, Condello C
• Cryo-EM Structures Reveal Tau Filaments from Down Syndrome Adopt Alzheimer's Disease Fold.
  bioRxiv : the preprint server for biology 2024 Ghosh U, Tse E, Yang H, Shi M, Carlo CD, Wang F, Merz GE, Prusiner SB, Southworth DR, Condello C
• Amyloid Accelerator Polyphosphate Implicated as the Mystery Density in α-Synuclein Fibrils.
  bioRxiv : the preprint server for biology 2024 Huettemann P, Mahadevan P, Lempart J, Tse E, Dehury B, Edwards BFP, Southworth DR, Sahoo BR, Jakob U
• Design principles to tailor Hsp104 therapeutics.
  bioRxiv : the preprint server for biology 2024 Lin J, Carman PJ, Gambogi CW, Kendsersky NM, Chuang E, Gates SN, Yokom AL, Rizo AN, Southworth DR, Shorter J
• Mapping interactions of calmodulin and neuronal NO synthase by crosslinking and mass spectrometry.
  The Journal of biological chemistry 2023 Felker D, Lee K, Pospiech TH, Morishima Y, Zhang H, Lau M, Southworth DR, Osawa Y
• The p97/VCP adaptor UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.
  Nature structural & molecular biology 2023 Braxton JR, Altobelli CR, Tucker MR, Tse E, Thwin AC, Arkin MR, Southworth DR
• Structural insights of the p97/VCP AAA+ ATPase: How adapter interactions coordinate diverse cellular functionality.
  The Journal of biological chemistry 2023 Braxton JR, Southworth DR
• Phosphorylation of a Cleaved Tau Proteoform at a Single Residue Inhibits Binding to the E3 Ubiquitin Ligase, CHIP.
  bioRxiv : the preprint server for biology 2023 Nadel CM, Wucherer K, Oehler A, Thwin AC, Basu K, Callahan MD, Southworth DR, Mordes DA, Craik CS, Gestwicki JE
• The E3 Ubiquitin Ligase, CHIP/STUB1, Inhibits Aggregation of Phosphorylated Proteoforms of Microtubule-associated Protein Tau (MAPT).
  Journal of molecular biology 2023 Nadel CM, Thwin AC, Callahan M, Lee K, Connelly E, Craik CS, Southworth DR, Gestwicki JE
• Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments.
  Nature communications 2023 Merz GE, Chalkley MJ, Tan SK, Tse E, Lee J, Prusiner SB, Paras NA, DeGrado WF, Southworth DR
• Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly.
  bioRxiv : the preprint server for biology 2023 Braxton JR, Shao H, Tse E, Gestwicki JE, Southworth DR
• The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.
  bioRxiv : the preprint server for biology 2023 Braxton JR, Altobelli CR, Tucker MR, Tse E, Thwin AC, Arkin MR, Southworth DR
• Chemical Features of Polyanions Modulate Tau Aggregation and Conformational States.
  Journal of the American Chemical Society 2023 Montgomery KM, Carroll EC, Thwin AC, Quddus AY, Hodges P, Southworth DR, Gestwicki JE
• Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3.
  Cell reports 2022 Cupo RR, Rizo AN, Braun GA, Tse E, Chuang E, Gupta K, Southworth DR, Shorter J
• Cryo-EM structures reveal dramatic remodeling of the p97 hexamer by the multi-domain adapter UBXD1.
  Acta Crystallographica Section A: Foundations and advances 2022 Julian Braxton, Chad Altobelli, Michelle Arkin, Daniel Southworth
• Structural and mechanistic studies of Skd3 (human CLPB) provide insight into disease-causing mutations and reveal unique AAA+ oligomerization.
  Biophysical Journal 2022 Alexandrea Rizo, Ryan R. Cupo, James Shorter, Daniel R. Southworth
• Structural basis for client engagement and chaperone cycling by human mitochondrial Hsp60.
  Biophysical Journal 2022 Julian R. Braxton, Jason E. Gestwicki, Daniel R. Southworth
• Structural basis for recognition of the Hsp90 closed, ATP state by the TPR-containing co-chaperone FKBP51.
  Alzheimer's & Dementia 2021 Kanghyun Lee, Aye Thwin, Eric Tse, Stephanie Gates, Daniel Southworth
• Assembly principles of the human R2TP chaperone complex reveal the presence of R2T and R2P complexes.
  Structure (London, England : 1993) 2021 Seraphim TV, Nano N, Cheung YWS, Aluksanasuwan S, Colleti C, Mao YQ, Bhandari V, Young G, Höll L, Phanse S, Gordiyenko Y, Southworth DR, Robinson CV, Thongboonkerd V, Gava LM, Borges JC, Babu M, …
• The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state.
  Molecular cell 2021 Lee K, Thwin AC, Nadel CM, Tse E, Gates SN, Gestwicki JE, Southworth DR
• CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.
  Research square 2021 Gupta M, Azumaya CM, Moritz M, Pourmal S, Diallo A, Merz GE, Jang G, Bouhaddou M, Fossati A, Brilot AF, Diwanji D, Hernandez E, Herrera N, Kratochvil HT, Lam VL, Li F, Li Y, Nguyen HC, Nowotny C, …
• CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.
  bioRxiv : the preprint server for biology 2021 Gupta M, Azumaya CM, Moritz M, Pourmal S, Diallo A, Merz GE, Jang G, Bouhaddou M, Fossati A, Brilot AF, Diwanji D, Hernandez E, Herrera N, Kratochvil HT, Lam VL, Li F, Li Y, Nguyen HC, Nowotny C, …
• Practical considerations for using K3 cameras in CDS mode for high-resolution and high-throughput single particle cryo-EM.
  Journal of structural biology 2021 Sun M, Azumaya CM, Tse E, Bulkley DP, Harrington MB, Gilbert G, Frost A, Southworth D, Verba KA, Cheng Y, Agard DA
• Conformational Plasticity of the Clpap Aaa+ Protease Couples Protein Unfolding and Proteolysis.
  Biophysical Journal 2021 Alexandrea N. Rizo, Kyle Eric Lopez, James Shorter, Daniel R. Southworth
• Structural Basis for Recognition of the Hsp90 Closed, ATP State by the TPR-Containing Co-Chaperone FKBP51.
  Biophysical Journal 2021 Kanghyun Lee, Aye Thwin, Daniel R. Southworth
• Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
  Science (New York, N.Y.) 2020 Gordon DE, Hiatt J, Bouhaddou M, Rezelj VV, Ulferts S, Braberg H, Jureka AS, Obernier K, Guo JZ, Batra J, Kaake RM, Weckstein AR, Owens TW, Gupta M, Pourmal S, Titus EW, Cakir M, Soucheray M, McGregor…
• Practical Considerations of Using the K3 Camera in CDS Mode for High-resolution and High-throughput Single Particle Cryo-EM.
  Microscopy and Microanalysis 2020 Ming Sun, Caleigh Azumaya, Eric Tse, Daniel Southworth, Kliment Verba, Adam Frost, Yifan Cheng, David Agard
• Conformational plasticity of the ClpAP AAA+ protease couples protein unfolding and proteolysis.
  Nature structural & molecular biology 2020 Lopez KE, Rizo AN, Tse E, Lin J, Scull NW, Thwin AC, Lucius AL, Shorter J, Southworth DR
• Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation.
  The Journal of biological chemistry 2019 Chen JJ, Nathaniel DL, Raghavan P, Nelson M, Tian R, Tse E, Hong JY, See SK, Mok SA, Hein MY, Southworth DR, Grinberg LT, Gestwicki JE, Leonetti MD, Kampmann M
• Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity.
  Life science alliance 2019 Lempart J, Tse E, Lauer JA, Ivanova MI, Sutter A, Yoo N, Huettemann P, Southworth D, Jakob U
• Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity.
  Cell reports 2019 Tariq A, Lin J, Jackrel ME, Hesketh CD, Carman PJ, Mack KL, Weitzman R, Gambogi C, Hernandez Murillo OA, Sweeny EA, Gurpinar E, Yokom AL, Gates SN, Yee K, Sudesh S, Stillman J, Rizo AN, Southworth DR,…
• Spiraling in Control: Structures and Mechanisms of the Hsp104 Disaggregase.
  Cold Spring Harbor perspectives in biology 2019 Shorter J, Southworth DR
• Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase.
  Nature communications 2019 Rizo AN, Lin J, Gates SN, Tse E, Bart SM, Castellano LM, DiMaio F, Shorter J, Southworth DR
• Allosteric Regulation of Oligomerization by a B12 Trafficking G-Protein Is Corrupted in Methylmalonic Aciduria.
  Cell chemical biology 2019 Ruetz M, Campanello GC, McDevitt L, Yokom AL, Yadav PK, Watkins D, Rosenblatt DS, Ohi MD, Southworth DR, Banerjee R
• Chaperone activation and client binding of a 2-cysteine peroxiredoxin.
  Nature communications 2019 Teixeira F, Tse E, Castro H, Makepeace KAT, Meinen BA, Borchers CH, Poole LB, Bardwell JC, Tomás AM, Southworth DR, Jakob U
• Cryo-EM Structural Analysis of Neuronal Nitric Oxide Synthase.
  Biophysical Journal 2019 Thomas H. Pospiech, Yoshihiro Morishima, Yoichi Osawa, Daniel R. Southworth
• Competing protein-protein interactions regulate binding of Hsp27 to its client protein tau.
  Nature communications 2018 Freilich R, Betegon M, Tse E, Mok SA, Julien O, Agard DA, Southworth DR, Takeuchi K, Gestwicki JE
• Polyphosphate Stabilizes Protein Unfolding Intermediates as Soluble Amyloid-like Oligomers.
  Journal of molecular biology 2018 Yoo NG, Dogra S, Meinen BA, Tse E, Haefliger J, Southworth DR, Gray MJ, Dahl JU, Jakob U
• Chaperone Activity and Dimerization Properties of Hsp90α and Hsp90β in Glucocorticoid Receptor Activation by the Multiprotein Hsp90/Hsp70-Dependent Chaperone Machinery.
  Molecular pharmacology 2018 Morishima Y, Mehta RK, Yoshimura M, Lau M, Southworth DR, Lawrence TS, Pratt WB, Nyati MK, Osawa Y
• The full-length cytochrome P450 enzyme CYP102A1 dimerizes at its reductase domains and has flexible heme domains for efficient catalysis.
  The Journal of biological chemistry 2018 Zhang H, Yokom AL, Cheng S, Su M, Hollenberg PF, Southworth DR, Osawa Y
• X-linked inhibitor of apoptosis protein (XIAP) is a client of heat shock protein 70 (Hsp70) and a biomarker of its inhibition.
  The Journal of biological chemistry 2017 Cesa LC, Shao H, Srinivasan SR, Tse E, Jain C, Zuiderweg ERP, Southworth DR, Mapp AK, Gestwicki JE
• Switch I-dependent allosteric signaling in a G-protein chaperone-B12 enzyme complex.
  The Journal of biological chemistry 2017 Campanello GC, Lofgren M, Yokom AL, Southworth DR, Banerjee R
• Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104.
  Science (New York, N.Y.) 2017 Gates SN, Yokom AL, Lin J, Jackrel ME, Rizo AN, Kendsersky NM, Buell CE, Sweeny EA, Mack KL, Chuang E, Torrente MP, Su M, Shorter J, Southworth DR
• Aggregation of Mod5 is affected by tRNA binding with implications for tRNA gene-mediated silencing.
  FEBS letters 2017 Read DF, Waller TJ, Tse E, Southworth DR, Engelke DR, Smaldino PJ
• THE STRUCTURAL BASIS FOR POLYPEPTIDE TRANSLOCATION BY THE HSP104 DISAGGREGASE.
  The FASEB Journal 2017 Daniel R Southworth, Adam Yokom, Stephanie Gates, Meredith Jackerel, James Shorter
• BAG3 Is a Modular, Scaffolding Protein that physically Links Heat Shock Protein 70 (Hsp70) to the Small Heat Shock Proteins.
  Journal of molecular biology 2016 Rauch JN, Tse E, Freilich R, Mok SA, Makley LN, Southworth DR, Gestwicki JE
• Polyphosphate: A Conserved Modifier of Amyloidogenic Processes.
  Molecular cell 2016 Cremers CM, Knoefler D, Gates S, Martin N, Dahl JU, Lempart J, Xie L, Chapman MR, Galvan V, Southworth DR, Jakob U
• Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation.
  Nature structural & molecular biology 2016 Yokom AL, Gates SN, Jackrel ME, Mack KL, Su M, Shorter J, Southworth DR
• Architecture and Nucleotide-Dependent Conformational Changes of the Rvb1-Rvb2 AAA+ Complex Revealed by Cryoelectron Microscopy.
  Structure (London, England : 1993) 2016 Ewens CA, Su M, Zhao L, Nano N, Houry WA, Southworth DR
• Single-particle cryo-electron microscopy of macromolecular complexes.
  Microscopy (Oxford, England) 2015 Skiniotis G, Southworth DR
• Specific Binding of Tetratricopeptide Repeat Proteins to Heat Shock Protein 70 (Hsp70) and Heat Shock Protein 90 (Hsp90) Is Regulated by Affinity and Phosphorylation.
  Biochemistry 2015 Assimon VA, Southworth DR, Gestwicki JE
• A conserved histidine modulates HSPB5 structure to trigger chaperone activity in response to stress-related acidosis.
  eLife 2015 Rajagopal P, Tse E, Borst AJ, Delbecq SP, Shi L, Southworth DR, Klevit RE
• Enhancement of dynamin polymerization and GTPase activity by Arc/Arg3.1.
  Biochimica et biophysica acta 2015 Byers CE, Barylko B, Ross JA, Southworth DR, James NG, Taylor CA, Wang L, Collins KA, Estrada A, Waung M, Tassin TC, Huber KM, Jameson DM, Albanesi JP
• Mitochondrial peroxiredoxin functions as crucial chaperone reservoir in Leishmania infantum.
  Proceedings of the National Academy of Sciences of the United States of America 2015 Teixeira F, Castro H, Cruz T, Tse E, Koldewey P, Southworth DR, Tomás AM, Jakob U
• The protein targeting factor Get3 functions as ATP-independent chaperone under oxidative stress conditions.
  Molecular cell 2014 Voth W, Schick M, Gates S, Li S, Vilardi F, Gostimskaya I, Southworth DR, Schwappach B, Jakob U
• Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles.
  Cell 2014 Kirschke E, Goswami D, Southworth D, Griffin PR, Agard DA
• Architecture of the nitric-oxide synthase holoenzyme reveals large conformational changes and a calmodulin-driven release of the FMN domain.
  The Journal of biological chemistry 2014 Yokom AL, Morishima Y, Lau M, Su M, Glukhova A, Osawa Y, Southworth DR
• KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated β-TrCP1 degradation.
  Neoplasia (New York, N.Y.) 2014 Shukla S, Allam US, Ahsan A, Chen G, Krishnamurthy PM, Marsh K, Rumschlag M, Shankar S, Whitehead C, Schipper M, Basrur V, Southworth DR, Chinnaiyan AM, Rehemtulla A, Beer DG, Lawrence TS, Nyati MK, …
• The molecular chaperone Hsp70 activates protein phosphatase 5 (PP5) by binding the tetratricopeptide repeat (TPR) domain.
  The Journal of biological chemistry 2013 Connarn JN, Assimon VA, Reed RA, Tse E, Southworth DR, Zuiderweg ER, Gestwicki JE, Sun D
• The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex.
  Biochemistry 2013 Smith MC, Scaglione KM, Assimon VA, Patury S, Thompson AD, Dickey CA, Southworth DR, Paulson HL, Gestwicki JE, Zuiderweg ER
• The conserved arginine 380 of Hsp90 is not a catalytic residue, but stabilizes the closed conformation required for ATP hydrolysis.
  Protein science : a publication of the Protein Society 2012 Cunningham CN, Southworth DR, Krukenberg KA, Agard DA
• Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex.
  Molecular cell 2011 Southworth DR, Agard DA
• High-Q nanomechanics via destructive interference of elastic waves.
  Physical review letters 2011 Wilson-Rae I, Barton RA, Verbridge SS, Southworth DR, Ilic B, Craighead HG, Parpia JM
• Grp94, the endoplasmic reticulum Hsp90, has a similar solution conformation to cytosolic Hsp90 in the absence of nucleotide.
  Protein science : a publication of the Protein Society 2009 Krukenberg KA, Böttcher UM, Southworth DR, Agard DA
• pH-dependent conformational changes in bacterial Hsp90 reveal a Grp94-like conformation at pH 6 that is highly active in suppression of citrate synthase aggregation.
  Journal of molecular biology 2009 Krukenberg KA, Southworth DR, Street TO, Agard DA
• Species-dependent ensembles of conserved conformational states define the Hsp90 chaperone ATPase cycle.
  Molecular cell 2008 Southworth DR, Agard DA
• Mutational analysis of S12 protein and implications for the accuracy of decoding by the ribosome.
  Journal of molecular biology 2007 Sharma D, Cukras AR, Rogers EJ, Southworth DR, Green R
• Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements.
  Cell 2006 Shiau AK, Harris SF, Southworth DR, Agard DA
• EF-G-independent reactivity of a pre-translocation-state ribosome complex with the aminoacyl tRNA substrate puromycin supports an intermediate (hybrid) state of tRNA binding.
  RNA (New York, N.Y.) 2004 Sharma D, Southworth DR, Green R
• Demonstration of the role of the DnaK chaperone system in assembly of 30S ribosomal subunits using a purified in vitro system.
  RNA (New York, N.Y.) 2003 Maki JA, Southworth DR, Culver GM
• Ribosomal translocation: sparsomycin pushes the button.
  Current biology : CB 2003 Southworth DR, Green R
• Ribosomal proteins S12 and S13 function as control elements for translocation of the mRNA:tRNA complex.
  Molecular cell 2003 Cukras AR, Southworth DR, Brunelle JL, Culver GM, Green R
• EFG-independent translocation of the mRNA:tRNA complex is promoted by modification of the ribosome with thiol-specific reagents.
  Journal of molecular biology 2002 Southworth DR, Brunelle JL, Green R