Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease

Madushi Raththagala; M. Kathryn Brewer; Matthew W. Parker; Amanda R. Sherwood; Brian K. Wong; Simon Hsu; Travis M. Bridges; Bradley C. Paasch; Lance M. Hellman; Satrio Husodo; David A. Meekins; Adam O. Taylor; Benjamin D. Turner; Kyle D. Auger; Vikas V. Dukhande; Srinivas Chakravarthy; Pascual Sanz; Virgil L. Woods; Sheng Li; Craig W. Vander Kooi; Matthew S. Gentry

doi:10.1016/j.molcel.2014.11.020

Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease

Madushi Raththagala, M. Kathryn Brewer, Matthew W. Parker, Amanda R. Sherwood, Brian K. Wong, Simon Hsu, Travis M. Bridges, Bradley C. Paasch, Lance M. Hellman, Satrio Husodo, David A. Meekins, Adam O. Taylor, Benjamin D. Turner, Kyle D. Auger, Vikas V. Dukhande, Srinivas Chakravarthy, Pascual Sanz, Virgil L. Woods, Sheng Li, Craig W. Vander KooiMatthew S. Gentry

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.

Original language	English
Pages (from-to)	261-272
Number of pages	12
Journal	Molecular Cell
Volume	57
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2014.11.020
State	Published - Jan 22 2015

Bibliographical note

Funding Information:
We thank Drs. Mike Begley, Carolyn Worby, Skip Waechter, Carlos Roma-Mateo, Pablo Sanchez-Martin, and Yvonne Fondufe-Mittendorf for assistance and advice, as well as Drs. Carol Beach, Jing Chen, and Martin Chow of the UK COBRE Center for Molecular Medicine Proteomics and Protein Analytical Core. This study was supported by NIH Grants R01NS070899 (M.S.G.), P20GM103486 (M.S.G. and C.W.V.K), R01AI081982 (S.L. and V.L.W.), R01GM020501 (S.L. and V.L.W.), TL1RR033172 (A.R.S.), P41GM103622 (S.C.), DE-AC02-06CH11357 (Advanced Photon Source), and R01AI101436 (S.L. and V.L.W); KSEF Grants KSEF-2268-RDE-014 and KSEF-2971-RDE-017 (M.S.G.); Mizutani Foundation for Glycoscience Award (M.S.G.); NSF Grant IIA-1355438 (M.S.G.); University of Notre Dame Office of Research (L.M.H.); and SAF2011-27442 grant from the Spanish Ministry of Economy (P.S.). M.S.G. and C.W.V.K. are founders of OptiMol Enzymes LLC.

Publisher Copyright:
© 2015 Elsevier Inc.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2014.11.020

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Raththagala, M., Brewer, M. K., Parker, M. W., Sherwood, A. R., Wong, B. K., Hsu, S., Bridges, T. M., Paasch, B. C., Hellman, L. M., Husodo, S., Meekins, D. A., Taylor, A. O., Turner, B. D., Auger, K. D., Dukhande, V. V., Chakravarthy, S., Sanz, P., Woods, V. L., Li, S., ... Gentry, M. S. (2015). Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease. Molecular Cell, 57(2), 261-272. https://doi.org/10.1016/j.molcel.2014.11.020

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title = "Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease",

abstract = "Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.",

author = "Madushi Raththagala and Brewer, {M. Kathryn} and Parker, {Matthew W.} and Sherwood, {Amanda R.} and Wong, {Brian K.} and Simon Hsu and Bridges, {Travis M.} and Paasch, {Bradley C.} and Hellman, {Lance M.} and Satrio Husodo and Meekins, {David A.} and Taylor, {Adam O.} and Turner, {Benjamin D.} and Auger, {Kyle D.} and Dukhande, {Vikas V.} and Srinivas Chakravarthy and Pascual Sanz and Woods, {Virgil L.} and Sheng Li and {Vander Kooi}, {Craig W.} and Gentry, {Matthew S.}",

note = "Funding Information: We thank Drs. Mike Begley, Carolyn Worby, Skip Waechter, Carlos Roma-Mateo, Pablo Sanchez-Martin, and Yvonne Fondufe-Mittendorf for assistance and advice, as well as Drs. Carol Beach, Jing Chen, and Martin Chow of the UK COBRE Center for Molecular Medicine Proteomics and Protein Analytical Core. This study was supported by NIH Grants R01NS070899 (M.S.G.), P20GM103486 (M.S.G. and C.W.V.K), R01AI081982 (S.L. and V.L.W.), R01GM020501 (S.L. and V.L.W.), TL1RR033172 (A.R.S.), P41GM103622 (S.C.), DE-AC02-06CH11357 (Advanced Photon Source), and R01AI101436 (S.L. and V.L.W); KSEF Grants KSEF-2268-RDE-014 and KSEF-2971-RDE-017 (M.S.G.); Mizutani Foundation for Glycoscience Award (M.S.G.); NSF Grant IIA-1355438 (M.S.G.); University of Notre Dame Office of Research (L.M.H.); and SAF2011-27442 grant from the Spanish Ministry of Economy (P.S.). M.S.G. and C.W.V.K. are founders of OptiMol Enzymes LLC. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

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Raththagala, M, Brewer, MK, Parker, MW, Sherwood, AR, Wong, BK, Hsu, S, Bridges, TM, Paasch, BC, Hellman, LM, Husodo, S, Meekins, DA, Taylor, AO, Turner, BD, Auger, KD, Dukhande, VV, Chakravarthy, S, Sanz, P, Woods, VL, Li, S, Vander Kooi, CW & Gentry, MS 2015, 'Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease', Molecular Cell, vol. 57, no. 2, pp. 261-272. https://doi.org/10.1016/j.molcel.2014.11.020

TY - JOUR

T1 - Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease

AU - Raththagala, Madushi

AU - Brewer, M. Kathryn

AU - Parker, Matthew W.

AU - Sherwood, Amanda R.

AU - Wong, Brian K.

AU - Hsu, Simon

AU - Bridges, Travis M.

AU - Paasch, Bradley C.

AU - Hellman, Lance M.

AU - Husodo, Satrio

AU - Meekins, David A.

AU - Taylor, Adam O.

AU - Turner, Benjamin D.

AU - Auger, Kyle D.

AU - Dukhande, Vikas V.

AU - Chakravarthy, Srinivas

AU - Sanz, Pascual

AU - Woods, Virgil L.

AU - Li, Sheng

AU - Vander Kooi, Craig W.

AU - Gentry, Matthew S.

N1 - Funding Information: We thank Drs. Mike Begley, Carolyn Worby, Skip Waechter, Carlos Roma-Mateo, Pablo Sanchez-Martin, and Yvonne Fondufe-Mittendorf for assistance and advice, as well as Drs. Carol Beach, Jing Chen, and Martin Chow of the UK COBRE Center for Molecular Medicine Proteomics and Protein Analytical Core. This study was supported by NIH Grants R01NS070899 (M.S.G.), P20GM103486 (M.S.G. and C.W.V.K), R01AI081982 (S.L. and V.L.W.), R01GM020501 (S.L. and V.L.W.), TL1RR033172 (A.R.S.), P41GM103622 (S.C.), DE-AC02-06CH11357 (Advanced Photon Source), and R01AI101436 (S.L. and V.L.W); KSEF Grants KSEF-2268-RDE-014 and KSEF-2971-RDE-017 (M.S.G.); Mizutani Foundation for Glycoscience Award (M.S.G.); NSF Grant IIA-1355438 (M.S.G.); University of Notre Dame Office of Research (L.M.H.); and SAF2011-27442 grant from the Spanish Ministry of Economy (P.S.). M.S.G. and C.W.V.K. are founders of OptiMol Enzymes LLC. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/1/22

Y1 - 2015/1/22

N2 - Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.

AB - Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.

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U2 - 10.1016/j.molcel.2014.11.020

DO - 10.1016/j.molcel.2014.11.020

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AN - SCOPUS:84921567531

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SP - 261

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JO - Molecular Cell

JF - Molecular Cell

IS - 2

ER -

Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease

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