Daniel Southworth, PhD

Professor
[email protected]
[email protected]

Our lab focuses on understanding molecular chaperone-driven protein quality control mechanisms that facilitate protein folding and cellular stress responses.  A protein must fold into a native state or a range of three-dimensional states in order to carry out biological functions, and must retain a certain degree of flexibility to accommodate various chemistries and binding events. This variation in structure makes the study of protein dynamics challenging yet essential in understanding the mechanism of chaperones and other molecular machines that are critical to proteome function and maintenance. We specialize in cryo-electron microscopy to obtain high-resolution snapshots of these macromolecular complexes in action.

Southworth Lab @ UCSF

Publications: 

Design principles to tailor Hsp104 therapeutics.

Cell reports

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

Aparna Unnikrishnan, Emily J Connelly, Dong hee Chung, Cory M Nadel, Aye Thwin, Charles S Craik, Daniel Southworth

Cryo-EM structure of a novel a-synuclein filament subtype from multiple system atrophy.

FEBS letters

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

Samelson AJ, Ariqat N, McKetney J, Rohanitazangi G, Bravo CP, Goodness D, Tian R, Grosjean P, Abskharon R, Eisenberg D, Kanaan NM, Gan L, Condello C, Swaney DL, Kampmann M

Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils.

PLoS biology

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

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

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

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

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

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

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

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

Braxton JR, Altobelli CR, Tucker MR, Tse E, Thwin AC, Arkin MR, 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

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

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

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

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

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

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

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

Julian Braxton, Chad Altobelli, Michelle Arkin, Daniel Southworth

Structural basis for client engagement and chaperone cycling by human mitochondrial Hsp60.

Biophysical journal

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

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)

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, Barbosa LRS, Ramos CHI, Kukura P, Houry WA

The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state.

Molecular cell

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

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, Owens TW, Peters JK, Rizo AN, Schulze-Gahmen U, Smith AM, Young ID, Yu Z, Asarnow D, Billesbølle C, Campbell MG, Chen J, Chen KH, Chio US, Dickinson MS, Doan L, Jin M, Kim K, Li J, Li YL, Linossi E, Liu Y, Lo M, Lopez J, Lopez KE, Mancino A, Moss FR, Paul MD, Pawar KI, Pelin A, Pospiech TH, Puchades C, Remesh SG, Safari M, Schaefer K, Sun M, Tabios MC, Thwin AC, Titus EW, Trenker R, Tse E, Tsui TKM, Wang F, Zhang K, Zhang Y, Zhao J, Zhou F, Zhou Y, Zuliani-Alvarez L, QCRG Structural Biology Consortium, Agard DA, Cheng Y, Fraser JS, Jura N, Kortemme T, Manglik A, Southworth DR, Stroud RM, Swaney DL, Krogan NJ, Frost A, Rosenberg OS, Verba KA

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

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, Owens TW, Peters JK, Rizo AN, Schulze-Gahmen U, Smith AM, Young ID, Yu Z, Asarnow D, Billesbølle C, Campbell MG, Chen J, Chen KH, Chio US, Dickinson MS, Doan L, Jin M, Kim K, Li J, Li YL, Linossi E, Liu Y, Lo M, Lopez J, Lopez KE, Mancino A, Moss FR, Paul MD, Pawar KI, Pelin A, Pospiech TH, Puchades C, Remesh SG, Safari M, Schaefer K, Sun M, Tabios MC, Thwin AC, Titus EW, Trenker R, Tse E, Tsui TKM, Wang F, Zhang K, Zhang Y, Zhao J, Zhou F, Zhou Y, Zuliani-Alvarez L, QCRG Structural Biology Consortium, Agard DA, Cheng Y, Fraser JS, Jura N, Kortemme T, Manglik A, Southworth DR, Stroud RM, Swaney DL, Krogan NJ, Frost A, Rosenberg OS, Verba KA

Practical considerations for using K3 cameras in CDS mode for high-resolution and high-throughput single particle cryo-EM.

Journal of structural biology

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

Alexandrea N. Rizo, Kyle Eric Lopez, James Shorter, Daniel R. Southworth

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

Science (New York, N.Y.)

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 M, Cakir Z, Jang G, O'Meara MJ, Tummino TA, Zhang Z, Foussard H, Rojc A, Zhou Y, Kuchenov D, Hüttenhain R, Xu J, Eckhardt M, Swaney DL, Fabius JM, Ummadi M, Tutuncuoglu B, Rathore U, Modak M, Haas P, Haas KM, Naing ZZC, Pulido EH, Shi Y, Barrio-Hernandez I, Memon D, Petsalaki E, Dunham A, Marrero MC, Burke D, Koh C, Vallet T, Silvas JA, Azumaya CM, Billesbølle C, Brilot AF, Campbell MG, Diallo A, Dickinson MS, Diwanji D, Herrera N, Hoppe N, Kratochvil HT, Liu Y, Merz GE, Moritz M, Nguyen HC, Nowotny C, Puchades C, Rizo AN, Schulze-Gahmen U, Smith AM, Sun M, Young ID, Zhao J, Asarnow D, Biel J, Bowen A, Braxton JR, Chen J, Chio CM, Chio US, Deshpande I, Doan L, Faust B, Flores S, Jin M, Kim K, Lam VL, Li F, Li J, Li YL, Li Y, Liu X, Lo M, Lopez KE, Melo AA, Moss FR, Nguyen P, Paulino J, Pawar KI, Peters JK, Pospiech TH, Safari M, Sangwan S, Schaefer K, Thomas PV, Thwin AC, Trenker R, Tse E, Tsui TKM, Wang F, Whitis N, Yu Z, Zhang K, Zhang Y, Zhou F, Saltzberg D

Practical Considerations of Using the K3 Camera in CDS Mode for High-resolution and High-throughput Single Particle Cryo-EM.

Microscopy and Microanalysis

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

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

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

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 a-Synuclein Proteotoxicity.

Cell reports

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, Shorter J

Spiraling in Control: Structures and Mechanisms of the Hsp104 Disaggregase.

Cold Spring Harbor perspectives in biology

Shorter J, Southworth DR

Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase.

Nature communications

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

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

Teixeira F, Tse E, Castro H, Makepeace KAT, Meinen BA, Borchers CH, Poole LB, Bardwell JC, Tomás AM, Southworth DR, Jakob U

Competing protein-protein interactions regulate binding of Hsp27 to its client protein tau.

Nature communications

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

Yoo N, Dogra S, Meinen BA, Tse E, Haefliger J, Southworth DR, Gray MJ, Dahl JU, Jakob U

Chaperone Activity and Dimerization Properties of Hsp90a and Hsp90ß in Glucocorticoid Receptor Activation by the Multiprotein Hsp90/Hsp70-Dependent Chaperone Machinery.

Molecular pharmacology

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

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

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

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.)

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

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

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

Rauch JN, Tse E, Freilich R, Mok SA, Makley LN, Southworth DR, Gestwicki JE

Polyphosphate: A Conserved Modifier of Amyloidogenic Processes.

Molecular cell

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

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)

Ewens CA, Su M, Zhao L, Nano N, Houry WA, Southworth DR

Single-particle cryo-electron microscopy of macromolecular complexes.

Microscopy (Oxford, England)

Skiniotis G, Southworth DR

A conserved histidine modulates HSPB5 structure to trigger chaperone activity in response to stress-related acidosis.

eLife

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

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

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

Voth W, Schick M, Gates S, Li S, Vilardi F, Gostimskaya I, Southworth DR, Schwappach B, Jakob U

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

Yokom AL, Morishima Y, Lau M, Su M, Glukhova A, Osawa Y, Southworth DR

KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated ß-TrCP1 degradation.

Neoplasia (New York, N.Y.)

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, Ray D

The molecular chaperone Hsp70 activates protein phosphatase 5 (PP5) by binding the tetratricopeptide repeat (TPR) domain.

The Journal of biological chemistry

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

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

Cunningham CN, Southworth DR, Krukenberg KA, Agard DA

High-Q nanomechanics via destructive interference of elastic waves.

Physical review letters

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

Krukenberg KA, Böttcher UM, Southworth DR, Agard DA

Mutational analysis of S12 protein and implications for the accuracy of decoding by the ribosome.

Journal of molecular biology

Sharma D, Cukras AR, Rogers EJ, Southworth DR, Green R

Ribosomal translocation: sparsomycin pushes the button.

Current biology : CB

Southworth DR, Green R

Ribosomal proteins S12 and S13 function as control elements for translocation of the mRNA:tRNA complex.

Molecular cell

Cukras AR, Southworth DR, Brunelle JL, Culver GM, Green R

Primary Department or Unit: 
Institute for Neurodegenerative Diseases