Daniel Southworth, PhD

Associate Professor

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


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

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.


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.


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

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