Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.1.18 (branching enzyme)
 628 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lafora progressive myoclonus epilepsy, caused by defective laforin or malin, insidiously present in normal teenagers with cognitive decline, followed by rapidly intractable epilepsy, dementia and death. Pathology reveals neurodegeneration with neurofibrillary tangle formation and Lafora bodies (LBs). LBs are deposits of starch-like polyglucosans, insufficiently branched and hence insoluble glycogen molecules resulting from glycogen synthase (GS) overactivity relative to glycogen branching enzyme activity. We previously made the unexpected observation that laforin, in the absence of which polyglucosans accumulate, specifically binds polyglucosans. This suggested that laforin's role is to detect polyglucosan appearances during glycogen synthesis and to initiate mechanisms to downregulate GS. Glycogen synthase kinase 3 (GSK3) is the principal inhibitor of GS. Dephosphorylation of GSK3 at Ser 9 activates GSK3 to inhibit GS through phosphorylation at multiple sites. Glucose-6-phosphate is a potent allosteric activator of GS. Glucose-6-phosphate levels are high when the amount of glucose increases and its activation of GS overrides any phospho-inhibition. Here, we show that laforin is a GSK3 Ser 9 phosphatase, and therefore capable of inactivating GS through GSK3. We also show that laforin interacts with malin and that malin is an E3 ubiquitin ligase that binds GS. We propose that laforin, in response to appearance of polyglucosans, directs two negative feedback pathways: polyglucosan-laforin-GSK3-GS to inhibit GS activity and polyglucosan-laforin-malin-GS to remove GS through proteasomal degradation.
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PMID:Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. 1611 20

Misregulation of the E3 ubiquitin ligase Parkin and the kinase PINK1 underlie both inherited and idiopathic Parkinson's disease-associated neurodegeneration. Parkin and PINK1 work together to catalyze the assembly of ubiquitin chains on substrates located on the outer mitochondrial membrane to facilitate autophagic removal of damaged mitochondria through a process termed mitophagy. Quantitative measurements of Parkin-mediated chain assembly, both in vitro and on mitochondria, have revealed that chains are composed of Lys6, Lys11, Lys48, and Lys63 linkages. The combinatorial nature of these chains is further expanded by the ability of PINK1 to phosphorylate individual subunits. The precise architecture of chains produced by the coordinated action of PINK1 and Parkin, however, are unknown. Here, we demonstrate that quantitative middle-down mass spectrometry using uniformly 15N-labeled ubiquitin variants as internal standards informs on the extent of chain branching. We find that Parkin is a prolific branching enzyme in vitro. Quantitative middle-down mass spectrometry also reveals that phospho-Ser65-ubiquitin (pSer65-Ub)-a key activator of Parkin-is not incorporated into chains to a significant extent. Our results suggest that Parkin-mediated chain branching is "on-pathway", and branch points are the principal targets of the deubiquitinase USP30.
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PMID:Quantitative Middle-Down MS Analysis of Parkin-Mediated Ubiquitin Chain Assembly. 3229 15