Matthew S. Gentry

Bio / Education: 

B.S.: University of Evansville
Ph.D.: Syracuse University with Dr. Richard L. Hallberg
Postdoc: UC-San Diego with Dr. Jack E. Dixon

Lab website: http://gentrylab.com/wordpress/

Research Description: 

Our lab studies the role of signal transduction machinery, namely phosphatases and E3 ubiquitin ligases, in neurodegenerative disease and biofuels research. We utilize a multidisciplinary approach that addresses and/or employs methodologies of cell biology, biochemistry, neurodegenerative diseases, genetics, bioinformatics, and phylogenetic relationships in vertebrate and protozoan model organisms, but relies heavily on cell biology and biochemistry. These applications employ model organisms and tissue culture cells to study basic cell metabolism, which have direct relevance to progressive myoclonus epilepsy and starch-based biofuels.

The lab is focused on two main research areas that are linked by glucan phosphatases. First, we study fundamental questions addressing the nature and mechanisms of glycogen metabolism and how mis-regulation of these signaling events leads to the neurodegenerative epilepsy called Lafora disease (LD). LD is similar to Parkinson's, Alzheimer's, and Huntington's in that patients with any of these diseases produce inclusion bodies. This work is funded by an NINDS R01. This project is centered on the regulation, signaling, and dynamics of the glucan phosphatase laforin, which is mutated in LD. Second, we study the role of glucan phosphatases in starch metabolism in plants and algae, and this work is funded by an NSF CAREER award. One goal of this project is to determine how glucan phosphatases could be harnessed in starch-based industrial manufacturing and biofuels. Thus, our work uniquely links neurodegeneration with biofuels research.

Humans develop insoluble glycogen particles, called Lafora bodies, as a result of the recessive neurodegenerative disorder called Lafora disease (LD). LD presents as a seizure in the second decade of the patient’s life and ends with death within ten years. The frequency and severity of the patient’s epilepsy increase with age and with the accumulation and size of LBs. Thus, it is hypothesized that LBs are the causative agent of the patient’s epilepsy and eventually the death of the patient. LD is the result of mutations in either the gene encoding the phosphatase laforin or the E3 ubiquitin ligase malin. One focus of our lab is to determine how the phosphatase laforin and the ubiquitin ligase malin regulate glycogen metabolism and inhibit Lafora disease.

Laforin was previously thought to only be conserved in vertebrates; however, we recently identified laforin orthologs in five unicellular eukaryotes (i.e. protists). Surprisingly, the biochemical composition of LBs closely resembles that of floridean starch; an insoluble carbohydrate synthesized by the same protists that have laforin. We demonstrated a direct correlation between the presence of laforin and synthesis of insoluble carbohydrates amongst protists. Additionally, we demonstrated that a plant protein called SEX4 is a functional equivalent of laforin. Strikingly, mutations in SEX4 result in a starch excess phenotype very reminiscent to LD. These insights led us to define laforin as the first member of a unique group of phosphatases called glucan phosphatases.

As the major energy cache in plants and algae, starch is a central component of human and animal food and a key constituent in many manufacturing processes. Additionally, starch is both a first-generation biofuel and it is vital to future efforts focused on microalgal hydrogen and oil production. Growing starch demand has impacted the drastic rise in corn prices from $85/metric ton in 2002 to $258 in 2012. Therefore, elucidation of pathways controlling starch metabolism is needed in order to develop novel strategies that manipulate them and satisfy the growing starch demand. A key pathway regulating starch metabolism - and one that is required for starch degradation - is reversible phosphorylation of glucose residues in starch outer glucans, rendering the granule surface accessible to glucan hydrolyzing enzymes.The focus of my lab towards these efforts is to determine the molecular mechanisms of glucan phosphatases. We are defining the function, dynamics, structures, and regulation of the glucan phosphatases as well as generating and evaluating engineered glucan phosphatases. Cumulatively, these studies will provide a comprehensive profile of how substrate specificity is determined as well as how glucans influence enzyme activity, providing the needed insights for current and future biotechnological exploitation of these enzymes. This work is a new effort in the lab and was initially funded by KSEF-2268-RDE-014 with recent funding secured from NSF CAREER MCB#1252345

We also demonstrated that malin is an E3 ubiquitin ligase that polyubiquitinates multiple proteins involved in glycogen synthesis, including laforin, protein targeting to glycogen (PTG), and glycogen debranching enzyme (AGL/GDE). Polyubiquitination is a cellular signal to degrade a protein. Thus, malin decreases glycogen accumulation by promoting the degradation of these, and other proteins.

Cumulatively, we propose that malin- and laforin-like activities are involved in an unstudied aspect of energy metabolism and that these functions are conserved from plants to protists to humans. Our goal is to untangle the intercalated events of metabolism, neurodegeneration, and epilepsy utilizing our insights from studying Lafora disease and plant starch metabolism.

Grants: 

1) Our work on Lafora disease is funded by the National Institute of Neurological Disorders and Stroke (NINDS), an institute within the NIH. The project number of our work is R01NS 070899 and titled, "Regulation, signaling, and dynamics of glucan phosphatases.

2) Additional work on Lafora disease was supported by an award from the Mizutani Foundation for Glycoscience.

3) Our work on glucan phosphatases in starch metabolism and biofuel production is funded by NSF CAREER Grant #1252345 through 2018.

4) Additional aspects of glucan phosphatases in plants and algae was funded by a Kentucky Science and Engineering Foundation (KSEF) award (KSEF-2268-RDE-014).

PubMed Publications: 

  • Meekins, D.A.;Raththagala, M.;Husodo, S.;White, C.J.;Guo, H.F.;Kötting, O.;Vander Kooi, C.W.;Gentry, M.S. "Phosphoglucan-bound structure of starch phosphatase Starch Excess4 reveals the mechanism for C6 specificity." Proceedings of the National Academy of Sciences of the United States of America 111, 20 (2014): 7272-7. [PubMed Link] | [ Full text ]
  • Jang, E.R.;Shi, P.;Bryant, J.;Chen, J.;Dukhante, V.;Gentry, M.S.;Jang, H.;Jeoung, M.;Galperin, E. "HUWE1 is a molecular link controlling RAF-1 activity supported by the Shoc2 scaffold." Molecular and cellular biology (2014): [PubMed Link] | [ Full text ]
  • Brewer, M.K.;Husodo, S.;Dukhande, V.V.;Johnson, M.B.;Gentry, M.S. "Expression, purification and characterization of soluble red rooster laforin as a fusion protein in Escherichia coli." BMC biochemistry 15, 1 (2014): 8. [PubMed Link] | [ Full text ]
  • Meekins, D.A.;Guo, H.F.;Husodo, S.;Paasch, B.C.;Bridges, T.M.;Santelia, D.;Kötting, O.;Vander Kooi, C.W.;Gentry, M.S. "Structure of the Arabidopsis glucan phosphatase like sex four2 reveals a unique mechanism for starch dephosphorylation." The Plant cell 25, 6 (2013): 2302-14. [PubMed Link] | [ Full text ]
  • Gentry, M.S.;Romá-Mateo, C.;Sanz, P. "Laforin, a protein with many faces: glucan phosphatase, adapter protein, et alii." The FEBS journal 280, 2 (2013): 525-37. [PubMed Link] | [ Full text ]
  • Sherwood, A.R.;Johnson, M.B.;Delgado-Escueta, A.V.;Gentry, M.S. "A bioassay for Lafora disease and laforin glucan phosphatase activity." Clinical biochemistry 46, 18 (2013): 1869-76. [PubMed Link] | [ Full text ]
  • Sherwood, A.R.;Paasch, B.C.;Worby, C.A.;Gentry, M.S. "A malachite green-based assay to assess glucan phosphatase activity." Analytical biochemistry 435, 1 (2013): 54-6. [PubMed Link] | [ Full text ]
  • Sánchez-Martín, P.;Raththagala, M.;Bridges, T.M.;Husodo, S.;Gentry, M.S.;Sanz, P.;Romá-Mateo, C. "Dimerization of the glucan phosphatase laforin requires the participation of cysteine 329." PloS one 8, 7 (2013): e69523. [PubMed Link] | [ Full text ]
  • Romá-Mateo, C.;Sanz, P.;Gentry, M.S. "Deciphering the role of malin in the lafora progressive myoclonus epilepsy." IUBMB life 64, 10 (2012): 801-8. [PubMed Link] | [ Full text ]
  • DePaoli-Roach, A.A.;Segvich, D.M.;Meyer, C.M.;Rahimi, Y.;Worby, C.A.;Gentry, M.S.;Roach, P.J. "Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity." Human molecular genetics 21, 7 (2012): 1604-10. [PubMed Link] | [ Full text ]
  • Romá-Mateo, C.;Solaz-Fuster Mdel, C.;Gimeno-Alcañiz, J.V.;Dukhande, V.V.;Donderis, J.;Worby, C.A.;Marina, A.;Criado, O.;Koller, A.;Rodriguez De Cordoba, S.;Gentry, M.S.;Sanz, P. "Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase." The Biochemical journal 439, 2 (2011): 265-75. [PubMed Link] | [ Full text ]
  • Santelia, D.;Kötting, O.;Seung, D.;Schubert, M.;Thalmann, M.;Bischof, S.;Meekins, D.A.;Lutz, A.;Patron, N.;Gentry, M.S.;Allain, F.H.;Zeeman, S.C. "The phosphoglucan phosphatase like sex Four2 dephosphorylates starch at the C3-position in Arabidopsis." The Plant cell 23, 11 (2011): 4096-111. [PubMed Link] | [ Full text ]
  • Romá-Mateo, C.;Moreno, D.;Vernia, S.;Rubio, T.;Bridges, T.M.;Gentry, M.S.;Sanz, P. "Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level." BMC evolutionary biology 11, (2011): 225. [PubMed Link] | [ Full text ]
  • Dukhande, V.V.;Rogers, D.M.;Romá-Mateo, C.;Donderis, J.;Marina, A.;Taylor, A.O.;Sanz, P.;Gentry, M.S. "Laforin, a dual specificity phosphatase involved in Lafora disease, is present mainly as monomeric form with full phosphatase activity." PloS one 6, 8 (2011): e24040. [PubMed Link] | [ Full text ]
  • Mui, M.Z.;Roopchand, D.E.;Gentry, M.S.;Hallberg, R.L.;Vogel, J.;Branton, P.E. "Adenovirus protein E4orf4 induces premature APCCdc20 activation in Saccharomyces cerevisiae by a protein phosphatase 2A-dependent mechanism." Journal of virology 84, 9 (2010): 4798-809. [PubMed Link] | [ Full text ]
  • Vander Kooi, C.W.;Taylor, A.O.;Pace, R.M.;Meekins, D.A.;Guo, H.F.;Kim, Y.;Gentry, M.S. "Structural basis for the glucan phosphatase activity of Starch Excess4." Proceedings of the National Academy of Sciences of the United States of America 107, 35 (2010): 15379-84. [PubMed Link] | [ Full text ]
  • Hsu, S.;Kim, Y.;Li, S.;Durrant, E.S.;Pace, R.M.;Woods VL, J.;Gentry, M.S. "Structural insights into glucan phosphatase dynamics using amide hydrogen-deuterium exchange mass spectrometry." Biochemistry 48, 41 (2009): 9891-902. [PubMed Link] | [ Full text ]
  • Gentry, M.S.;Pace, R.M. "Conservation of the glucan phosphatase laforin is linked to rates of molecular evolution and the glucan metabolism of the organism." BMC evolutionary biology 9, (2009): 138. [PubMed Link] | [ Full text ]
  • Kötting, O.;Santelia, D.;Edner, C.;Eicke, S.;Marthaler, T.;Gentry, M.S.;Comparot-Moss, S.;Chen, J.;Smith, A.M.;Steup, M.;Ritte, G.;Zeeman, S.C. "STARCH-EXCESS4 is a laforin-like Phosphoglucan phosphatase required for starch degradation in Arabidopsis thaliana." The Plant cell 21, 1 (2009): 334-46. [PubMed Link] | [ Full text ]
  • Gentry, M.S.;Dixon, J.E.;Worby, C.A. "Lafora disease: insights into neurodegeneration from plant metabolism." Trends in biochemical sciences 34, 12 (2009): 628-39. [PubMed Link] | [ Full text ]
  • Worby, C.A.;Gentry, M.S.;Dixon, J.E. "Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG)." The Journal of biological chemistry 283, 7 (2008): 4069-76. [PubMed Link] | [ Full text ]
  • Cheng, A.;Zhang, M.;Gentry, M.S.;Worby, C.A.;Dixon, J.E.;Saltiel, A.R. "A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease." Genes & development 21, 19 (2007): 2399-409. [PubMed Link] | [ Full text ]
  • Gentry, M.S.;Dowen RH, 3rd;Worby, C.A.;Mattoo, S.;Ecker, J.R.;Dixon, J.E. "The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease." The Journal of cell biology 178, 3 (2007): 477-88. [PubMed Link] | [ Full text ]
  • Kim, Y.;Gentry, M.S.;Harris, T.E.;Wiley, S.E.;Lawrence JC, J.;Dixon, J.E. "A conserved phosphatase cascade that regulates nuclear membrane biogenesis." Proceedings of the National Academy of Sciences of the United States of America 104, 16 (2007): 6596-601. [PubMed Link] | [ Full text ]
  • Worby, C.A.;Gentry, M.S.;Dixon, J.E. "Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates." The Journal of biological chemistry 281, 41 (2006): 30412-8. [PubMed Link] | [ Full text ]
  • Gentry, M.S.;Worby, C.A.;Dixon, J.E. "Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin." Proceedings of the National Academy of Sciences of the United States of America 102, 24 (2005): 8501-6. [PubMed Link] | [ Full text ]
  • Gentry, M.S.;Li, Y.;Wei, H.;Syed, F.F.;Patel, S.H.;Hallberg, R.L.;Pallas, D.C. "A novel assay for protein phosphatase 2A (PP2A) complexes in vivo reveals differential effects of covalent modifications on different Saccharomyces cerevisiae PP2A heterotrimers." Eukaryotic cell 4, 6 (2005): 1029-40. [PubMed Link] | [ Full text ]
  • Dobbelaere, J.;Gentry, M.S.;Hallberg, R.L.;Barral, Y. "Phosphorylation-dependent regulation of septin dynamics during the cell cycle." Developmental cell 4, 3 (2003): 345-57. [PubMed Link] | [ Full text ]
  • Gentry, M.S.;Hallberg, R.L. "Localization of Saccharomyces cerevisiae protein phosphatase 2A subunits throughout mitotic cell cycle." Molecular biology of the cell 13, 10 (2002): 3477-92. [PubMed Link] | [ Full text ]
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