Paul FitzGerald, Ph.D.
Professor and Chair
Dean's Endowed Chair in Medical Research
3420 Tupper Hall
The lens of the eye has the unusual biological requirement to be optically clear. How that is achieved is not fully understood, but a very high degree of structural order and uniformity is considered essential.
We have identified two proteins that are very divergent members of the intermediate filament family of proteins that assemble into a unique cytoskeletal element called the beaded filament. Both of these proteins and the beaded filament are expressed only in the lens.
Using genetic engineering approaches we created mice that lack the beaded filament proteins, in an effort to determine beaded filament function. The lenses of these animals were able to develop and differentiate normally, achieving the high degree of structural order that characterizes the lens, but they were unable to maintain that order with age. Thus the structural order seen in the lens is inherently unstable, and the beaded filament serves to confer resistance to the age-dependent loss of structure.
We are now focused on determining how the beaded filament accomplishes its mission:
- What is the structure of the filament?
- What proteins link it to the plasma membrane?
- What membrane proteins is it linked to?
- What membrane domains are formed at these sites?
The study of beaded filament structure has lead to a more general consideration of intermediate filament structure. Toward this end we have adapted site directed spin labeling and electron paramagnetic resonance to the study of its structure.
Research Support - Principal Investigator
- NIH R01 EY08747-19 Molecular Analysis of Ocular Lens Beaded Filaments. Through July 31, 2011.
- NIH R01 EY015560-3 SDSL EPR Study of Intermediate Filament Structure. Through March 31, 2011.
- NIH P30 EY12576-01-05 Vision Research Core Grant. Through July 1, 2009 (Renewal Submitted). PI: Leo Chalupa, Microscopy Module Director: Paul FitzGerald
FitzGerald, Paul, Ning Sun, Brad Shibata, and John Hess. Expression of the type VI intermediate filament proteins CP49 and filensin in the mouse lens epithelium. Mol Vis. 2016 Aug 6;22:970-89. eCollection 2016. PMID: 27559293
Dr. Catherine Cheng , Ms. Roberta B. Nowak , Dr. Sondip K. Biswas , Dr. Woo-Kuen Lo , Dr. Paul FitzGerald, Velia Fowler. Tropomodulin 1 regulation of actin is required for the formation of large paddle protrusions between mature lens fiber cells, IOVS 2016 Aug 1;57(10):4084-99
Liu, Lishan; Hess, John; Sahu, Indra; FitzGerald, Paul; McCarrick, Robert; Lorigan, Gary. Probing the Local Secondary Structure of Human Vimentin with Electron Spin Echo Envelope Modulation (ESEEM) Spectroscopy Journal of Physical Chemistry. J. Phys. Chem. B, 2016, 120 (48), pp 12321–12326
Ron Ofri, Christopher Reilly, David Maggs, Paul FitzGerald, Yael Shilo-Benjamini, Kathryn Good, Robert Grahn, Danielle Splawski, and Leslie Lyons Characterization of a novel, early-onset, autosomal recessive, progressive retinal degeneration in Bengal cats. Invest Ophthalmol Vis Sci. 2015 Aug 1;56(9):5299-308.
S Kumari, Ph.D.; Neha Gupta; Alan Shiels, Ph.D.; Paul G FitzGerald, Ph.D.; Anil G Menon , Ph.D.; Richard T Mathias. Role of Aquaporin 0 in lens biomechanics. Biochem Biophys Res Commun. 2015 Jul 10;462(4):339-45.
Ning Sun, Brad Shibata, John F. Hess and Paul G. FitzGerald. An alternative means of retaining ocular structure and improving immunoreactivity for light microscopy studies. Mol Vis. 2016;21:428-42
Emily Levine; Azhar Zam; Pengfei Zhang; Alina Pechko; Xinlei Wang; Paul FitzGerald; Edward N Pugh, Jr.; Robert J Zawadzki; Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1 Vision Res. 2014 Sep;102:71-9.
Jacquelyn Gerhart, Marvin Greenbaum, Victoria Scheinfeld, Paul FitzGerald. Mitchell Crawford, Arturo Bravo-Nuevo, Meghan Pitts, and Mindy George-Weinstein. Myo/Nog Cells: Targets for Preventing the Accumulation of Skeletal 1 Muscle-Like Cells in the Human Lens PLoS (in Press March 26, 2014)
Abby L Manthey; Salil A Lachke; Paul G FitzGerald; Robert W Mason; David A Scheiblin; John H McDonald; Melinda K Duncan, Ph.D. Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development. Mechanisms in Development 2014 Feb;131:86-110
Stewart DN, Lango J, Nambiar KP, Falso MJ, FitzGerald PG, Rocke DM, Hammock BD, Buchholz BA Carbon turnover in the water-soluble protein of the adult human lens. Mol Vis. 2013;19:463-75. Epub 2013 Feb 25. PMC # 3580966
Hess, J. F., Budamagunta, M., S., Aziz, A., FitzGerald, P. G*., & Voss, J. C. Electron paramagnetic resonance analysis of the vimentin tail domain reveals points of order in a largely disordered region and conformational adaptation upon filament assembly. Protein Science, 2013 Jan;22(1), 47-55. PMID: 23109052. PMCID: PMC3575859. *Corresponding Author
*Aziz, A., Hess, J. F., Budamagunta, M. S., Voss, J. C., Kuzin, A. P., Huang, Y. J., Xiao, R., Montelione, G. T., FitzGerald, P**., Hunt, J. F. (2012). The structure of vimentin linker 1 and rod 1B domains characterized by site-directed spin-labeling electron paramagnetic resonance (SDSL-EPR) and x-ray crystallography. Journal of Biological Chemistry, 287, 28349-28361. PMCID: PMC3436525. * Selected by PSI Nature Structural Biology as a featured advance in structural biology ** Corresponding Author
Fudge, D.S., McCuaig, J.V.,Van Stralen, S., Hess, J.F., Wang, H., Mathias, R., and FitzGerald, P.G. Intermediate filaments regulate tissue size and stiffness in the murine lens. Investigative Ophthalmology and Visual Science. 2011 Jun 1;52(6):3860-7.
John J. Castorino, Shannon M. Gallagher-Colombo, Alex Levin, Paul G. FitzGerald, Jessica Polishook1, Barbara Kloeckener-Gruissem, Eric Ostertag, and Nancy J. Philp. Truncation Mutation of solute carrier SLC16A12 associated juvenile cataract impairs trafficking of the protein to the plasma membrane. Human Molecular Genetics. 2011 In submission
Daniel N. Stewart, Krishnan P. Nambiar, Jozsef Lango, Miranda J. Sarachine, Paul G. FitzGerald, David M.Rocke, Bruce D. Hammock, and Bruce A. Buchholz. Protein Turnover in the Adult Human Lens. Experimental Eye Research. In submission.
Atya Aziz, John F. Hess, Madhu S. Budamagunta, John C. Voss and Paul G. J. SDSL EPR Determination of Vimentin Head Domain Structure. Biological Chemistry 2010 285:15278-85.
Lindstrom SH, Nacsa N, Blankenship T, Fitzgerald PG, Weller C, Vaney DI, Wilson M. Distribution and structure of efferent synapses in the chicken retina. Vis Neurosci. 2009 Mar-Apr;26(2):215-26.
Atya Aziz, John F. Hess, Madhu S. Budamagunta, Paul G. FitzGerald* and John C. Voss. Head and Rod 1 Interactions in Vimentin: Identification of contact sites, structure and changes with phosphorylation using Site Directed Spin Labeling and Electron Paramagnetic Resonance. J. Biological Chemistry, 2009 Mar 13;284:7330-8. *Corresponding Author.
Fitzgerald, Paul G. Lens Intermediate Filaments. Experimental Eye Research, 2009 Feb;8:165–172. Review Article, with original data, Peer Reviewed.
Yoon, Kyoung-hye and FitzGerald, P.G. Periplakin serves as a linker for both vimentin and the highly divergent beaded filament proteins in the ocular lens. Investigative Opthalmology and Visual Science. 2009 Mar;50:1283-9.
Josh Pittenger, John Hess, Madhu Budamagunta, John Voss and Paul FitzGerald. SDSL EPR characterization of phosphorylation-induced structural changes in vimentin. Intermediate Filaments Biochemistry. 2008 Oct;47:10863-70.
Yoon, Kyoung-hye, Tom Blankenship, Bradley Shibata and Paul FitzGerald. Resisting the effects of aging: A function for the fiber cell beaded filament. Investigative Ophthalmology and Visual Science. 2008 Mar;49:130-6.
Pittenger, J.T., Hess, J. F. and FitzGerald, P.G. Identifying the role of specific motifs in the lens fiber cell-specific intermediate filament protein phakosin. Investigative Opthalmology and Visual Science. 2007 Nov;48:5132-41.
Lagerstedt, Jens; Cavigiolio, Giorgio; Roberts, Linda; Hong, Hyun-Seok; Jin, Lee-Way; FitzGerald, Paul; Oda, Michael; Voss, John. Mapping the Structural Transition in an amyloidogenic apolipoprotien A-I. Biochemistry. 2007 Aug 28;46:9693-9699
Madhu Budamagunta, John Hess, Paul FitzGerald and John Voss. Describing the structure and assembly of protein filaments by EPR spectroscopy of spin labeled side chains. Cell Biochem and Biophys. 2007;48:45-53
Blankenship, T, Bradshaw, L, Shibata, B, and FitzGerald P. Structural specializations emerging late in mouse lens fiber cell differentiation. Investigative Ophthalmology and Visual Science 2007 Jul;48: 3269-3276.
John F. Hess, Madhu S. Budamagunta, Rebecca L. Shipman, Paul G. FitzGerald, John C. Voss. Characterization of the linker 1-2 region in human vimentin using site directed spin labeling and electron paramagnetic resonance. Biochemistry 2006 Oct 3; 45:11737-43.
Hess, J. F., Voss, J. C. and FitzGerald, P.G. Vimentin production, purification, assembly and study by EPR. In "Cell Biology Protocols", 2006 edited by Harris Graham and Rickwood, published by John Wiley and sons, London, UK.
Hess, John., Madhu S. Budamagunta, Paul FitzGerald, John C. Voss. Characterization of structural changes in vimentin bearing an EBS-like mutation using site directed spin labeling and electron paramagnetic resonance. Journal of Biological Chemistry 2005 Jan 21;280:2141-6
- National Institutes of Health
- National Eye Institute
- University of California, Davis, Academic Senate Distinguished Teaching Award
- UC Davis School of Medicine, C. John Tupper Prize for Excellence in Teaching
- UC Davis School of Medicine, Kaiser Award for Excellence In Teaching Basic Sciences
- CHA402, Cell and Tissue Biology