The carbohydrate-binding domain of overexpressed STBD1 is important for its stability and protein–protein interactions

Zhu, Yan; Zhang, Mei; Kelly, Amber Renee; Cheng, Alan

doi:10.1042/bsr20140053

Cited by 27 publications

(34 citation statements)

References 39 publications

(68 reference statements)

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“…The respective reductions in liver and muscle AMPK protein levels observed with β1 W100A and β2 W98A KI mutation are consistent with the observed destabilisation and rapid degradation of starch-binding domain-containing protein 1 (STBD1), a glycogen-binding protein recently shown to be a substrate of AMPK [ 25 ], in response to mutating a conserved tryptophan residue (W293) within its CBM. In light of these relevant findings demonstrating STBD1 degradation and reduced interaction with glycogen-associated proteins induced by CBM tryptophan mutation [ 26 ], our data suggest that AMPK β1 and β2 glycogen binding via their respective CBM may preserve an AMPK pool, potentially protecting AMPK from destabilisation and cellular degradation. While relative gene expression levels of Prkab1 (AMPK β1) and Prkab2 (AMPK β2) were also reduced in livers and muscle from KI compared to respective WT mice, respective AMPK β subunit proteins were translated and detectable with functional AMPK α kinase activity in tissues from each genotype.…”

Section: Discussionmentioning

confidence: 63%

Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism

Hoffman

Whitfield

Janzen

et al. 2020

Molecular Metabolism

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Objective Glycogen is a major energy reserve in liver and skeletal muscle. The master metabolic regulator AMP-activated protein kinase (AMPK) associates with glycogen via its regulatory β subunit carbohydrate-binding module (CBM). However, the physiological role of AMPK-glycogen binding in energy homeostasis has not been investigated in vivo . This study aimed to determine the physiological consequences of disrupting AMPK-glycogen interactions. Methods Glycogen binding was disrupted in mice via whole-body knock-in (KI) mutation of either the AMPK β1 (W100A) or β2 (W98A) isoform CBM. Systematic whole-body, tissue and molecular phenotyping was performed in KI and respective wild-type (WT) mice. Results While β1 W100A KI did not affect whole-body metabolism or exercise capacity, β2 W98A KI mice displayed increased adiposity and impairments in whole-body glucose handling and maximal exercise capacity relative to WT. These KI mutations resulted in reduced total AMPK protein and kinase activity in liver and skeletal muscle of β1 W100A and β2 W98A, respectively, versus WT mice. β1 W100A mice also displayed loss of fasting-induced liver AMPK total and α-specific kinase activation relative to WT. Destabilisation of AMPK was associated with increased fat deposition in β1 W100A liver and β2 W98A skeletal muscle versus WT. Conclusions These results demonstrate that glycogen binding plays critical roles in stabilising AMPK and maintaining cellular, tissue and whole-body energy homeostasis.

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Section: Discussionmentioning

confidence: 63%

Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism

Hoffman

Whitfield

Janzen

et al. 2020

Molecular Metabolism

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“…) . STBD1 has recently been shown to interact with glycogen‐associated proteins, such as glycogen synthase, debranching enzyme, and laforin …”

Section: Glycogen Flux Pathways In the Heartmentioning

confidence: 99%

Myocardial glycogen dynamics: New perspectives on disease mechanisms

Chandramouli

Varma

Stevens

et al. 2015

Clin Exp Pharma Physio

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Cardiac glycogen regulation involves a complex interplay between multiple signalling pathways, allosteric activation of enzymes, and sequestration for autophagic degradation. Signalling pathways appear to converge on glycogen regulatory enzymes via insulin (glycogen synthase kinase 3β, protein phosphatase 1, allosteric action of glucose-6-phosphate), β-adrenergic (phosphorylase kinase protein phosphatase 1 inhibitor), and 5' adenosine monophosphate-activated protein kinase (allosteric action of glucose-6-phosphate, direct glycogen binding, insulin receptor). While cytosolic glycogen synthesis and breakdown are relatively well understood, recent findings relating to phagic glycogen degradation highlight a new area of investigation in the heart. It has been recently demonstrated that a specific glycophagy pathway is operational in the myocardium. Proteins involved in recruiting glycogen to the forming phagosome have been identified. Starch-binding domain-containing protein 1 is involved in binding glycogen and mediating membrane anchorage via interaction with a homologue of the phagosomal protein light-chain 3. Specifically, it has been shown that starch-binding domain-containing protein 1 and light-chain 3 have discrete phagosomal immunolocalization patterns in cardiomyocytes, indicating that autophagic trafficking of glycogen and protein cargo in cardiomyocytes can occur via distinct pathways. There is strong evidence from glycogen storage diseases that phagic/lysosomal glycogen breakdown is important for maintaining normal cardiac glycogen levels and does not simply constitute a redundant 'alternative' breakdown route for glycogen. Advancing understanding of glycogen handling in the heart is an important priority with relevance not only to genetic glycogen storage diseases but also to cardiac metabolic stress disorders such as diabetes and ischaemia.

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“…The N-terminal Transmembrane Region and the C-terminal CBM20 Domain Are Critical for Glycogen Transport to Lysosomes in Liver-Stbd1 has an N-terminal hydrophobic transmembrane region, a putative leucine zipper, an identified AIM, and a CBM20 (13,14,18). To determine critical elements in Stbd1 for glycogen transport to lysosomes, we constructed a series of AAV vectors to express WT human Stbd1 and its mutants in dKO mice ( Fig.…”

Section: Stbd1 Plays a Dominant Role In Transporting Glycogen Tomentioning

confidence: 99%

Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver

Sun¹,

Yi²,

Yang

et al. 2016

Journal of Biological Chemistry

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A small portion of cellular glycogen is transported to and degraded in lysosomes by acid ␣-glucosidase (GAA) in mammals, but it is unclear why and how glycogen is transported to the lysosomes. Stbd1 has recently been proposed to participate in glycogen trafficking to lysosomes. However, our previous study demonstrated that knockdown of Stbd1 in GAA knockout mice did not alter lysosomal glycogen storage in skeletal muscles. To further determine whether Stbd1 participates in glycogen transport to lysosomes, we generated GAA/Stbd1 double knock-out mice. In fasted double knock-out mice, glycogen accumulation in skeletal and cardiac muscles was not affected, but glycogen content in liver was reduced by nearly 73% at 3 months of age and by 60% at 13 months as compared with GAA knock-out mice, indicating that the transport of glycogen to lysosomes was suppressed in liver by the loss of Stbd1. Exogenous expression of human Stbd1 in double knock-out mice restored the liver lysosomal glycogen content to the level of GAA knock-out mice, as did a mutant lacking the Atg8 family interacting motif (AIM) and another mutant that contains only the N-terminal 24 hydrophobic segment and the C-terminal starch binding domain (CBM20) interlinked by an HA tag. Our results demonstrate that Stbd1 plays a dominant role in glycogen transport to lysosomes in liver and that the N-terminal transmembrane region and the C-terminal CBM20 domain are critical for this function.Liver and muscle are the two primary sites for glycogen metabolism in mammals. Glycogen is synthesized and mostly degraded in the cytoplasm, but a small percentage of glycogen is transported into the lysosomes and hydrolyzed by the enzyme acid ␣-glucosidase (GAA) 3 (1-3). Deficiency of GAA causes Pompe disease (glycogen storage disease type II), resulting in a progressive lysosomal glycogen accumulation and dysfunction in cardiac and skeletal muscle and other tissues (4 -6). Enzyme replacement therapy with recombinant human GAA is the only available therapy for this disorder to have remarkable success, but it also has significant limitations such as high titer antibody formation and difficulties in delivering the therapeutic protein to skeletal muscle tissues (7-11). A conceivable alternative way to treat Pompe disease would be to block the transport of cytoplasmic glycogen to the lysosomes. Thus, understanding how glycogen enters the lysosome is a critical step in finding new therapeutic targets for Pompe disease. It has been demonstrated that conventional autophagy (macroautophagy) plays an important role in the transport of glycogen to lysosomes in skeletal muscle (12). Specifically, knock-out of an autophagy key gene Atg7 resulted in a decrease of glycogen content by 50 -60% in skeletal muscles of GAA knock-out mice (12). This suggests that other routes exist for glycogen transport to lysosomes. In recent studies, starch binding domain-containing protein 1 (Stbd1) has gained attention for its potential involvement in glycogen transport. The Stbd1 protein contains a putat...

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The carbohydrate-binding domain of overexpressed STBD1 is important for its stability and protein–protein interactions

Cited by 27 publications

References 39 publications

Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism

Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism

Myocardial glycogen dynamics: New perspectives on disease mechanisms

Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver

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