About

Joseph Muretta, PhD, is an Assistant Professor at the University of Minnesota. His lab engineers proteins for applications in the biomedical sciences, utilizing foundations of structural biology, protein biochemistry, and physiology to develop new therapy concepts. His current work focuses on treatments for genetic diseases including Duchenne Muscular Dystrophy and cancer. Dr. Muretta's research investigates the molecular underpinnings of life and aims to develop engineered proteins for treating disease, with a particular emphasis on creating new antibodies and antibody-fusion proteins for cancer and gene therapy. His projects include studying dystrophin in muscular dystrophy, engineering protein allosteric modulators of cell surface receptors involved in immune cell differentiation, and developing therapeutic antibodies and fusion proteins for solid tumors and pediatric cancers. His team employs various approaches such as phage- and yeast-display protein engineering, high-throughput screening, recombinant protein expression, biophysical characterization, and structural determination techniques like X-ray crystallography and Cryo-EM. Dr. Muretta earned his PhD from the University of Nevada, Reno, in 2007.

Research topics

• Biology
• Chemistry
• Biophysics
• Cell biology
• Biochemistry
• Acoustics
• Computational biology
• Physics

Selected publications

• Multiple modes of AFM reveal distinct mechanical properties for dystrophin and utrophin not manifest by small fragments

  Proceedings of the National Academy of Sciences · 2026-01-14

  articleOpen access

  Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by the absence of the protein dystrophin. Dystrophin is hypothesized to work as a molecular shock absorber that limits myofiber membrane damage when undergoing reversible unfolding upon muscle stretching and contraction. Here, we report the mechanical characterization of single full-length dystrophin (Dys) molecules using two operational modes of atomic force microscopy; constant speed and constant force as well as Monte Carlo simulations. Furthermore, we have compared Dys with large fragments encoding the N-terminus through spectrin repeat 10 (DysN-R10), the C-terminal retinal isoform of dystrophin (Dp260), and full-length utrophin (Utr). Our comprehensive data reveal that Dys, DysN-R10, and Dp260, all show a uniform, brittle unfolding behavior, whereas Utr demonstrates more complex unfolding dominated by a stiffening spring behavior. These fundamentally different mechanical behaviors in vitro suggest different in vivo functions for Dys and Utr with implications for the potential efficacy of Utr upregulation to substitute for Dys deficiency in DMD.

  PublisherOA PDFDOI

• A Phosphorylation Switch Governs KIF11’s Mechanical Output During Mitosis

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-25

  articleOpen access

  The kinesin-5 motor protein KIF11 is crucial for mitotic spindle assembly, driving the separation of spindle poles through microtubule sliding. Src-family kinases phosphorylate KIF11 at multiple tyrosine residues within its motor domain, but the mechanistic consequences of these modifications remain unclear. Here, we dissect the role of phosphorylation at Y211 using phospho-mimetic (Y211E) and non-phosphorylatable mutants (Y211F) in biochemical, biophysical, and cellular assays. Optical trapping and Förster resonance energy transfer (FRET) analyses reveal that Y211 phosphorylation slows neck-linker docking, reducing motor velocity and force generation under load. In human cells, Y211E expression impairs bipolar spindle formation and decreases spindle pole separation velocity, while Y211F shortens steady-state spindle length. Fluorescence recovery after photobleaching (FRAP) analyses show that Y211E accelerates motor turnover on spindle microtubules, consistent with the mutant motor's heightened load sensitivity. Together, these findings support a model in which Src-mediated phosphorylation at Y211 acts as a rheostat to tune KIF11 mechanochemistry and spindle assembly dynamics, linking cancer-relevant kinase signaling to mitotic force generation.

  PublisherDOI

• The atomic structure of human dystrophin spectrin-like repeat 24

  Acta Crystallographica Section F Structural Biology Communications · 2026-04-20

  articleOpen accessSenior author

  The structure of spectrin-like repeat 24 of human dystrophin was determined at 2.5 Å effective resolution. The structure exhibits a three-helix bundle fold, common to all spectrin-repeat family members, and shares a high degree of homology with existing structures of spectrin-like repeat 1 from dystrophin and utrophin. The structure provides molecular details of the atomic interactions that stabilize the repeat, including hydrophobic interactions and inter-helix and intra-helix salt bridges. AlphaFold models of the repeat are in excellent agreement with the structure, showing an all-atom r.m.s.d. of 1.13 Å. Accurate modeling of SR24 supports AlphaFold modeling of all 24 of the dystrophin spectrin-like repeats and the use of these models in predicting the molecular determinants of dystrophin stability, a key aspect of its biological function as a structural protein that cross-links actin filaments to the dystrophin-glycoprotein complex to mediate a mechanical connection between the cytoskeleton and the extracellular matrix.

  PublisherDOI

• An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia

  Blood Neoplasia · 2025-05-19 · 1 citations

  articleOpen access

  B-lineage acute lymphoblastic leukemia (B-ALL) therapy is being transformed by therapies targeting antigens such as CD19, CD20, and CD22 on the surface of B-ALL cells. Moreover, having therapies targeting these different B-ALL antigens has helped address challenges associated with both intra- and inter-patient variability in targeted antigen expression levels and antigen loss as mechanisms of therapy resistances. To further expand the range of targetable antigens in B-ALL therapy, we developed a novel antibody-drug conjugate (ADC) that targets the VpreB1 (CD179a) component of the surrogate light chain. VpreB1 is expressed across most B-ALL molecular subtypes but otherwise has expression limited to precursor B cells, but not mature B cells. Our VpreB1 antibody demonstrated high affinity for its target protein and when conjugated to the toxin calicheamicin (VpreB1-ADC) exhibited significant in vitro toxicity against B-ALL cells harboring a range of genomic alterations. In vivo, the VpreB1-ADC was well tolerated in mice, with modest weight loss and decreased white blood cell counts. When tested against a B-ALL cell line and multiple B-ALL patient-derived xenograft models, the VpreB1-ADC significantly reduced leukemia burden, prolonged survival, and cured a subset of mice. These promising results support further investigation of the VpreB1 component of the surrogate light chain as a therapeutic target, including the VpreB1-ADC in preclinical and clinical trials, with the goal of expanding the arsenal of immunoconjugates available for the treatment of B-ALL.

  PublisherDOI

• Single-Chain Nanobody Inhibition of Notch and Avidity Enhancement Utilizing the β-Pore-Forming Toxin Aerolysin

  ACS Chemical Biology · 2025-03-13

  articleCorresponding

  Notch plays critical roles in developmental processes and disease pathogenesis, which have led to numerous efforts to modulate its function with small molecules and antibodies. Here we present a nanobody inhibitor of Notch signaling derived from a synthetic phage-display library targeting the Notch negative regulatory region (NRR). The nanobody inhibits Notch signaling in a luciferase reporter assay with an IC50 of about 5 μM and in a Notch-dependent hematopoietic progenitor cell differentiation assay, despite a modest 19 μM affinity for the Notch NRR. We addressed the low affinity by fusion to a mutant varient of the β-pore-forming toxin aerolysin, resulting in a significantly improved IC50 for Notch inhibition. The nanobody-aerolysin fusion inhibits proliferation of T-ALL cell lines with efficacy similar to that of other Notch pathway inhibitors. Overall, this study reports the development of a Notch inhibitory antibody and demonstrates a proof-of-concept for a generalizable strategy to increase the efficacy and potency of low-affinity antibody binders.

  PublisherDOI

• Supplementary Figure 2 from Desmoglein 2 Functions as a Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells

  2025-11-27

  articleOpen access

  <p>S2. Predicted orientation of the F57 side chain in the apoFABP4 form.</p>

  PublisherOA PDFDOI

• Supplementary Figure 1 from Desmoglein 2 Functions as a Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells

  2025-11-27

  articleOpen access

  <p>S1. DSC and DSG isoforms expressed in MCF-7 cells.</p>

  PublisherOA PDFDOI

• Human dystrophin tandem calponin homology actin-binding domain crystallized in a closed-state conformation

  Acta Crystallographica Section D Structural Biology · 2025-02-26 · 1 citations

  articleOpen accessSenior author

  The structure of the N-terminal actin-binding domain of human dystrophin was determined at 1.94 Å resolution. Each chain in the asymmetric unit exists in a `closed' conformation, with the first and second calponin homology (CH) domains directly interacting via a 2500.6 Å 2 interface. The positioning of the individual CH domains is comparable to the domain-swapped dimer seen in previous human dystrophin and utrophin actin-binding domain 1 structures. The CH1 domain is highly similar to the actin-bound utrophin structure and structural homology suggests that the `closed' single-chain conformation opens during actin binding to mitigate steric clashes between CH2 and actin.

  PublisherOA PDFDOI

• Supplementary Figure 2 from Desmoglein 2 Functions As A Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells

  2024-09-16

  preprintOpen access

  <p>S2. Predicted orientation of the F57 side chain in the apoFABP4 form.</p>

  PublisherDOI

• Supplementary Figure 1 from Desmoglein 2 Functions As A Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells

  2024-09-16

  preprintOpen access

  <p>S1. DSC and DSG isoforms expressed in MCF-7 cells.</p>

  PublisherDOI

Recent grants

• NIH Grant F32AR056191

  NIH · $145k · 2011

Frequent coauthors

• David D. Thomas

  University of Minnesota

  63 shared

• Adam Sheka

  Twin Cities Orthopedics

  18 shared

• Masato Yamamoto

  University of Minnesota

  18 shared

• Scott Kizy

  18 shared

• Keith M. Wirth

  18 shared

• Hisham Abdelwahab

  18 shared

• Sayeed Ikramuddin

  University of Minnesota

  18 shared

• Ann V. Hertzel

  17 shared

Awards & honors

• Dr. James E. Rubin Medical Memorial Award
• Graduating Medical Student Research Award
• Veneziale-Steer Award
• Dr. Marvin and Hadassah Bacaner Research Awards
• Schmidt Steer Award