James M. Ervasti, PhD

Professor, and Biophysics Department of Biochemistry, Molecular Biology

James M. Ervasti

Contact Info

jervasti@umn.edu

Office Phone 612-626-6517

Lab Phone 612-624-9294

Office Address:
7-104 MCB
420 Washington Avenue SE
Minneapolis, MN 55455

Lab Address:
7-102/7-224 Molecular and Cellular Biology Building (MCB)
420 Washington Avenue SE
Minneapolis, MN 55455

Professor, and Biophysics Department of Biochemistry, Molecular Biology

Faculty, PhD Program in Biochemistry, Molecular Biology and Biophysics

Faculty, PhD Program in Integrative Biology and Physiology

Faculty, PhD Program in Molecular, Cellular, Developmental Biology and Genetics

Preceptor, Medical Scientist Training Program (Combined MD/PhD Training Program)


PhD, University of Minnesota (1989)

Summary

Expertise

Dystrophin, Utrophin, Muscular dystrophy, Actin cytoskeleton, Microtubule-associated proteins, Protein-protein interactions, Protein stability, Animal models of disease

Research

Research Summary/Interests

My laboratory primarily studies the structure and cellular function of the dystrophin-glycoprotein complex, which spans the muscle cell plasma membrane (or sarcolemma) and links the cortical actin cytoskeleton with the extracellular matrix. Greater understanding of the physiologic role of the dystrophin-glycoprotein complex is necessary to understand how its absence or abnormality leads to Duchenne muscular dystrophy and forms of human dilated cardiomyopathy. The lab has defined the complete actin-binding region of 400 kDa dystrophin and shown that its homologue utrophin binds actin filaments through a distinct molecular mechanism. Novel methods to visualize the sarcolemmal cytoskeleton without interference from internal structures provided the first evidence that dystrophin functions in vivo to mechanically stabilize ?-actin filaments in costameres. Studies of dystrophin-deficient mice and new animal models generated by the lab have provided insight into the function of costameres in striated muscle and suggest novel links between dystrophin deficiency and alterations in cell signaling, or gene expression manifest by dystrophic muscle. My lab’s unique capability to express biochemical amounts of full-length dystrophin and utrophin has made possible new studies to i) characterize the effects of dystrophy-causing point mutations on dystrophin structure/function, ii) to identify novel associated proteins and iii) to develop new protein-based therapies for dystrophinopathies.

In a completely new line of investigation, my group is working to determine the potentially unique roles of non-muscle actin isoforms in the establishment/maintenance of cell polarity in a variety of tissues. The ?- and ?-isoforms of actin distribute to distinct locations within a variety of polarized cell types, including neurons, epithelial cells, and hair cells of the inner ear yet ?- and ?-actin differ from each other by only 4 amino acids. Using new isoform-specific reagents and conditional knock-out mouse lines developed during the course of our muscular dystrophy studies, the lab is now working to identify non-overlapping functions of these two highly conserved and widely expressed proteins.

Research Methods/Techniques

Research Description Our objective is to fully define the function of dystrophin in striated muscle to understand how its absence or abnormality leads to the pathologies observed in Duchenne and Becker muscular dystrophies. Our unique approach integrates biochemical and biophysical analyses of the very large dystrophin protein with in vivo assessments of its function in transgenic mouse models of muscular dystrophy. We have shown that dystrophin is a monomer that binds laterally along an actin filament through the concerted actions of two distinct and spatially separated actin binding sites and is necessary for strong mechanical coupling between the sarcolemma and costameric actin filaments. We have also demonstrated that the dystrophin homologue utrophin can substitute for dystrophin in coupling costameric actin filaments to the sarcolemma when transgenically overexpressed in dystrophin-deficient skeletal muscle and binds actin filaments with similar affinity as dystrophin, but through distinct modes of contact. Finally, we showed that dystrophin directly binds to microtubules and is required to organize the subsarcolemmal microtubule lattice of skeletal muscle. Several of these advances were made possible by methods that we pioneered to express and purify biochemical amounts of full-length recombinant dystrophin and utrophin. Continuing to build on the project’s history of innovation, we have developed new cell and animal models that enable us to investigate the critical roles of roles of cytoplasmic non-muscle actin isoforms in skeletal muscle. We are also investigating small molecule approaches to stabilize aberrant dystrophins expressed in some muscular dystrophy patients. Finally, we are also pursuing state-of-the-art in vivo rescue experiments and proteomic screens to further define the physiological role of microtubule lattice organization by dystrophin.

Publications

Recent Publications

  • Belanto, J.J., Mader, T., Eckhoff, M., Strandjord, D.M., Banks, G.B., Gardner, M.K., Lowe, D.A. and Ervasti J.M. (2014) Microtubule Binding Distinguishes Dystrophin from Utrophin. Proc Natl. Acad. Sci. USA 111:5723-5728. PMCID: PMC3992671
  • Perrin B.J., Strandjord, D.M., Narayanan, P., Henderson, D.M., Johnson, K.R. and Ervasti, J.M. (2013) ?-Actin and fascin-2 cooperate to maintain stereocilia length. J. Neurosci. 33:8114. PMCID: PMC3718021
  • Lin, A.Y., Prochniewicz, E., Henderson, D.M., Li, B., Ervasti, J.M. and Thomas, D.D. (2012) Impacts of dystrophin and utrophin domains on actin structural dynamics: implications for therapeutic design. J. Mol. Biol. 420:87-98. PMCID: PMC3367031
  • Henderson, D.M., Lin, A.Y., Thomas, D.D. and Ervasti, J.M. (2012) The Carboxy-Terminal Third of Dystrophin Enhances Actin Binding Activity. J. Mol. Biol. 416:414-424. PMCID: PMC3273627
  • Zhang, D.-S., Piazza, V., Perrin, B.J., Rzadzinska, A.K., Poczatek, J.C., Wang, M., Prosser, H.M., Ervasti, J.M., Corey, D.P. and Lechene, C.P. (2012) Multi-isotope imaging mass spectrometry reveals slow protein turnover in stereocilia of inner-ear hair cells. Nature 481:520–524. PMCID: PMC3267870
  • Baltgalvis, K.A., Jaeger, M.A., Fitzsimons, D.P., Thayer, S.A., Lowe, D.A. and Ervasti, J.M. (2011) Transgenic over-expression of ?-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice. Skeletal Muscle 1:32. PMCID: PMC3214766
  • Henderson, D.M., Belanto, J.J., Li, B., Heun-Johnson, H. and Ervasti, J.M. (2011) Internal deletion compromises the stability of dystrophin Hum. Mol. Genet. 20:2955-2963. PMCID: PMC3131041
  • Bunnell, T.M., Burbach, B.J., Shimizu, Y. and Ervasti, J.M. (2011) ?-actin specifically controls cell growth, migration and the G-actin pool. Mol. Biol. Cell 22:4047-4058. PMCID: PMC3204067
  • Prins, K.W., Call, J.A., Lowe, D.A and Ervasti, J.M. (2011) Quadriceps myopathy caused by skeletal muscle specific ablation of ?cyto-actin. J. Cell Sci. 124:951-957. PMCID: PMC3048892
  • Henderson, D.M., Lee, A. and Ervasti, J.M. (2010) Disease-Causing Missense Mutations in Actin Binding Domain 1 of Dystrophin Induce Thermodynamic Instability and Protein Aggregation. Proc. National Acad. Sci. USA 107:9632-9637. PMCID: PMC2906886
  • Perrin, B.J., Sonnemann, K.J and Ervasti, J.M. (2010) ?-actin and ?-actin are each dispensible for auditory hair cell development but required for stereocilia maintenance. PLoS Genetics 6:e1001158. PMCID: PMC2954897
  • Belyantseva, I.A., Perrin, B.J., Sonnemann, K.J., Zhu, M., Stepanyan, R., McGee, J., Frolenkov, G.A., Walsh, E.J., Friderici, K.H., Friedman, T.B. and Ervasti, J.M. (2009) ?-Actin is required for cytoskeletal maintenance but not development. Proc. National Acad. Sci. USA 106:9703-9708. PMCID: PMC2701000
  • Prins, K.W., Humston, J.M., Mehta, A., Tate, V., Ralston, E. and Ervasti, J.M. (2009) Dystrophin is a microtubule-associated protein J. Cell Biol. 186:363-369. PMCID: PMC2728405
  • Bunnell, T.M. and Ervasti, J.M. (2010) Delayed embryonic development and impaired cell growth and survival in Actg1 null mice. Cytoskeleton 67:564-572.
  • Henderson, D.M., Lee, A. and Ervasti, J.M. (2010) Disease-Causing Missense Mutations in Actin Binding Domain 1 of Dystrophin Induce Thermodynamic Instability and Protein Aggregation. Proc. National Acad. Sci. USA 107:9632-9637.
  • Prins, K.W., Humston, J.M., Mehta, A., Tate, V., Ralston, E. and Ervasti, J.M. (2009) Dystrophin is a microtubule-associated protein J. Cell Biol. 186:363-369.
  • Belyantseva, I.A., Perrin, B.J., Sonnemann, K.J., Zhu, M., Stepanyan, R., McGee, J., Frolenkov, G.A., Walsh, E.J., Friderici, K.H., Friedman, T.B. and Ervasti, J.M. (2009) ?-Actin is required for cytoskeletal maintenance but not development. Proc. National Acad. Sci. USA 106:9703-9708.
  • Sonnemann, K.J., Heun-Johnson, H., Turner A.J., Baltgalvis, K., Lowe D.A. and Ervasti, J.M. (2009) Functional substitution by TAT-utrophin in dystrophin deficient mice. PLoS Med. 6:e1000083. PDF
  • Prochniewicz, E., Henderson, D.M., Ervasti, J.M. and Thomas, D.D. (2009) Dystrophin and utrophin have distinct effects on the structural dynamics of actin Proc. National Acad. Sci. USA 106:7822-7827.
  • Jaeger, M.A., Sonnemann, K.J., Fitzsimons, D., Prins, K.W. and Ervasti, J.M. (2009) Context dependent functional substitution of a-skeletal actin by ?-cytoplasmic actin FASEB J. 23:2205-2214.
  • Bunnell, T.M., Jaeger M.A., Fitzsimons, D.P., Prins, K.W. and Ervasti, J.M. (2008) Destabilization of the dystrophin-glycoprotein complex without functional deficits in a-dystrobrevin null muscle PLoS One 3:e2604.
  • Prins K.W., Lowe D.A. and Ervasti, J.M. (2008) Skeletal muscle-specific ablation of ?cyto-actin does not exacerbate the mdx phenotype. PLoS One 3:e2419.
  • Ervasti, J.M. and Sonnemann, K.J. (2008) Biology of the Dystrophin-Glycoprotein Complex. In: International Review of Cytology; A Survey of Cell Biology (K.W. Jeon, ed.) Ch. 5, pp. 191-225, Elsevier, San Diego.
  • Ervasti, J.M. (2007) Dystrophin, its interactions with other proteins, and implications for muscular dystrophy. BBA Molec. Basis Dis. 1772:108-117 (Published online June 7, 2006 DOI 10.1016/j.bbadis.2006.05.010).