Dimeric Quaternary Structure of Human Laforin

Sankhala, Rajeshwer S.; Koksal, Adem C.; Ho, Lan; Nitschké, Felix; Minassian, Berge A.; Cingolani, Gino

doi:10.1074/jbc.m114.627406

Cited by 19 publications

(18 citation statements)

References 50 publications

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“…DXMS data confirm that the laforin dimerization interface is via the DSP domain. In contrast, another study determined the structure of laforin using a hybrid approach [67]. These investigations determined the X-ray crystal structure of the DSP domain, generated a homology model of the CBM, and performed small angle X-ray scattering on the full-length protein.…”

Section: Laforin Utilizes a Tetramodular Architecture And Cooperativitymentioning

confidence: 99%

Unique carbohydrate binding platforms employed by the glucan phosphatases

Emanuelle

Brewer

Meekins

et al. 2016

Cell. Mol. Life Sci.

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Glucan phosphatases are a family of enzymes that are functionally conserved at the enzymatic level in animals and plants. These enzymes bind and dephosphorylate glycogen in animals and starch in plants. While the enzymatic function is conserved, the glucan phosphatases employ distinct mechanisms to bind and dephosphorylate glycogen or starch. The founding member of the family is a bimodular human protein called laforin that is comprised of a carbohydrate binding module 20 (CBM20) followed by a dual specificity phosphatase domain. Plants contain two glucan phosphatases: Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2). SEX4 contains a chloroplast targeting peptide, dual specificity phosphatase (DSP) domain, a CBM45, and a carboxy-terminal motif. LSF2 is comprised of simply a chloroplast targeting peptide, DSP domain, and carboxy-terminal motif. SEX4 employs an integrated DSP-CBM glucan-binding platform to engage and dephosphorylate starch. LSF2 lacks a CBM and instead utilizes two surface binding sites to bind and dephosphorylate starch. Laforin is a dimeric protein in solution and it utilizes a tetramodular architecture and cooperativity to bind and dephosphorylate glycogen. This chapter describes the biological role of glucan phosphatases in glycogen and starch metabolism and compares and contrasts their ability to bind and dephosphorylate glucans.

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Section: Laforin Utilizes a Tetramodular Architecture And Cooperativitymentioning

confidence: 99%

Unique carbohydrate binding platforms employed by the glucan phosphatases

Emanuelle

Brewer

Meekins

et al. 2016

Cell. Mol. Life Sci.

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“…Mammals express a DSP called laforin as, if not functional, it is associated with the Lafora disease (Minassian et al 1998). The three-dimensional crystal structure of laforin has been elaborated only recently (Raththalaga et al 2015;Sankhala et al 2015). Patients suffering Lafora disease accumulate poorly branched but highly phosphorylated glycogen-like intracellular inclusions which are designated as Lafora bodies (Turnbull et al 2010).…”

Section: Sex4mentioning

confidence: 99%

Starch

2015

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“…57,58 In mammals, laforin has been found to bind various proteins involved in glycogen metabolism, including glycogen synthase, GSK3, and PTG. 63 63 …”

Section: Laforinmentioning

confidence: 99%

“…[59][60][61][62] Mutations in laforin can cause Lafora disease with abnormal accumulation of polyglucosan in various tissues, for example, the liver, skeletal muscle, heart, and brain (neurons). 63…”

Section: Laforinmentioning

confidence: 99%

Is liver glycogen fragility a possible drug target for diabetes?

Cheng

2019

FASEB j.

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Liver glycogen α particles are molecularly fragile in diabetic mice, and readily form smaller β particles, which degrade more rapidly to glucose. This effect is well associated with the loss of blood-glucose homeostasis in diabetes. The biological mechanism of such fragility is still unknown; therefore, there are perceived opportunities that could eventually lead to new means to manage type 2 diabetes. The hierarchical structures of glycogen particles are controlled by the underlying biosynthesis/degradation process that involves various enzymes, including, for example, glycogen synthase (GS) and glycogen-branching enzyme (GBE). Recent studies have shown that fragile glycogen α particles in diabetic mice have longer chains and a higher molecular density compared to wild-type mice, indicating an enhanced enzymatic activity ratio of GS to GBE in diabetes. Furthermore, it has been shown that with an improved blood glucose homeostasis, the glycogen fragility in diabetic mice can be restored by treatment with active ingredients from traditional Chinese medicine, yet the underlying mechanism is unknown. In this review, we summarize recent advances in understandings glycogen fragility from the perspectives of glycogen biosynthesis/degradation, glycogen hierarchical structures, and its relation to diabetes. Importantly, we for the first time set GS/GBE activity ratio as the therapeutic target for diabetes. K E Y W O R D Schain-length distribution, glycogen biosynthesis, glycogen degradation, particle size distribution 4 | LI and HU ACKNOWLEDGMENTSWe would like to thank Prof. Robert G. Gilbert (The University of Queensland) for his mentor guidance and intelligent work in the research field of studying molecular structure of glycogen. We would also like to thank the financial support from

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Dimeric Quaternary Structure of Human Laforin

Cited by 19 publications

References 50 publications

Unique carbohydrate binding platforms employed by the glucan phosphatases

Unique carbohydrate binding platforms employed by the glucan phosphatases

Starch

Is liver glycogen fragility a possible drug target for diabetes?

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