Research

Hsp90, Hsp60 and CHIP chaperone systems

Hsp90 progresses through a conserved ATPase cycle of conformational states, forming dynamic assemblies with distinct cochaperones to fold and activate clients, including kinases, hormone receptors and transcription factors. In mitochondria, the chaperonin Hsp60 folds newly imported and transiently misfolded proteins, while the E3 ligase CHIP directs Hsp70 and Hsp90 clients toward degradation.

• An FKBP51 helix extension that recognizes the Hsp90 C-terminal dimer and the client maturation state
• Dynamic apical domains that let mtHsp60 hold a substrate in its chamber while recruiting the mtHsp10 cap
• Recombinant Fabs that inhibit the E3 ubiquitin ligase CHIP through multiple mechanisms

Key papers Lee et al., Mol Cell 2021 · Braxton et al., Nat Struct Mol Biol 2024

With collaborators Chung et al., J Biol Chem 2025

AAA+ disaggregases and unfoldases

Hexameric AAA+ machines couple ATP hydrolysis to polypeptide translocation through a central channel, unfolding substrates and solubilizing aggregates, amyloids and prions. p97/VCP extracts proteins from assemblies and membranes, coordinated by more than 30 adapter proteins, and its dysfunction is linked to neurodegeneration and multisystem proteinopathy.

• A spiral Hsp104 hexamer whose pore-loop tyrosines grip substrate for hand-over-hand translocation
• Substrate gripping by ClpB, and three ClpAP translocation states that couple unfolding to proteolysis
• Structural features that govern the human mitochondrial disaggregase Skd3
• The adaptor UBXD1 opens the p97 ring through multi-domain tethered interactions

Key papers Yokom et al., Nat Struct Mol Biol 2016 · Gates et al., Science 2017 · Rizo et al., Nat Commun 2019 · Lopez et al., Nat Struct Mol Biol 2020 · Braxton et al., Nat Struct Mol Biol 2023

With collaborators Cupo et al., Cell Rep 2022

Reviews Shorter & Southworth, Cold Spring Harb Perspect Biol 2019 · Braxton & Southworth, J Biol Chem 2023

Tau and α-synuclein filaments

Tau and α-synuclein form amyloid filaments that are central diagnostic and therapeutic targets in Alzheimer's and Parkinson's disease, and filaments from different diseases adopt distinct folds. The lab determines filament structures directly from patient brain tissue; small molecules that discriminate among these folds could enable disease-specific diagnostics.

• Stacked binding of the PET tracer GTP-1 at a surface cleft of Alzheimer's tau filaments
• Tau filaments from Down syndrome brain that adopt the Alzheimer's disease fold
• A new α-synuclein filament subtype from multiple system atrophy

Key papers Merz et al., Nat Commun 2023

With collaborators Ghosh et al., Acta Neuropathol Commun 2024 · Yan et al., FEBS Lett 2025

Nitric oxide synthase

Mammalian nitric oxide synthase (NOS) generates nitric oxide, a signaling molecule in neurotransmission, inflammation and cardiovascular regulation. Catalysis depends on calmodulin-driven electron transfer from the reductase domain to the oxygenase domain that converts L-arginine to NO. With the Osawa lab, we study how domain motions in NOS and related cytochrome P450 enzymes direct electron flow.

• Large conformational changes and calmodulin-driven release of the FMN domain in full-length nNOS
• A full-length P450, CYP102A1, that dimerizes at its reductase domains and has flexible heme domains
• Crosslinking mass spectrometry maps of calmodulin–nNOS interactions

Key papers Yokom et al., J Biol Chem 2014

With collaborators Zhang et al., J Biol Chem 2018 · Felker et al., J Biol Chem 2023