Laforin

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Laforin
other names

Glucan phosphatase

Existing structure data : PDB  4R30 , PDB  4RKK

Properties of human protein
Mass / length primary structure 331 amino acids , 37,158 Da
Secondary to quaternary structure Homodimer
Identifier
External IDs
Enzyme classification
EC, category 3.1.3.-
Orthologue (human)
Entrez 7957
Ensemble ENSG00000112425
UniProt O95278
Refseq (mRNA) NM_001018041.1
Refseq (protein) NP_001018051.1
PubMed search 7957

Laforin is an enzyme from the group of protein tyrosine phosphatases . The physiological substrate of laforin has not yet been identified and the molecular mechanisms that cause Lafora disease are so far unknown.

properties

Laforin was first described in 1998. Laforin is a 331 amino acid protein. It serves to avoid excessive phosphorylation of glycogen , since otherwise insoluble and poorly branched aggregates of the hyperphosphorylated glycogen can arise.

Laforin is the gene EPM2A coded and is in almost all tissue types expressed . The enzyme is produced in cells of the heart , skeletal muscles , kidneys , pancreas and brain . The isoform 2 of Laforin has no enzyme activity and is probably an inhibitor of the isoforms 1 and 7. isoform 4 is additionally in the placenta formed. The enzyme contains two different domains . On the one hand the N -terminal domain (known as carbohydrate-binding module ), which recognizes and can bind carbohydrates. On the other hand the C -terminal domain (known as dual specificity phosphatase domain ), which is responsible for the catalysis of the chemical reaction. Laforin also regulates autophagocytosis with the help of the protein mTOR , which is impaired in Lafora's disease.

Continues to promote Laforin by binding to the E3 ubiquitin ligase Malin and Hsp70 the ubiquitination whereby the toxicity and thus the degradation of other enzymes of glycogen metabolism, misfolded proteins is diminished. Laforin is phosphorylated at a serine at position 25 by AMPK .

pathology

A mutation in the EPM2A gene leads to defects in the enzyme. This causes an abnormal accumulation of glucans , known as the Lafora bodies . A normal build-up of glycogen stores can no longer be guaranteed. Since Lafora bodies are often located in nerve cells , their accumulation damages the functions of the cells and this is particularly reflected in seizures . The energy supply is also disturbed by the lack of glycogen. In Lafora (corpuscle) disease (a glycogen storage disease ), it is changed on chromosome 6 (6q23 – q25) due to a genetic defect .

Web links

Individual evidence

  1. ↑ S. Ortolano, I. Vieitez, RC Agis-Balboa, C. Spuch: Loss of GABAergic cortical neurons under read the neuropathology of Lafora disease. In: Molecular brain. Volume 7, January 2014, p. 7, doi : 10.1186 / 1756-6606-7-7 , PMID 24472629 , PMC 3917365 (free full text).
  2. ↑ Minassian BA, Lee JR, Herbrick JA, et al .: Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. In: Nature Genetics . tape 20 , 1998, pp. 171-174 .
  3. ^ MA Sullivan, S. Nitschke, M. Steup, BA Minassian, F. Nitschke: Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan. In: International journal of molecular sciences. Volume 18, Number 8, August 2017, p., Doi : 10.3390 / ijms18081743 , PMID 28800070 .
  4. ^ PJ Roach: Glycogen phosphorylation and Lafora disease. In: Molecular aspects of medicine. Volume 46, December 2015, pp. 78-84, doi : 10.1016 / j.mam.2015.08.003 , PMID 26278984 , PMC 4663170 (free full text).
  5. ↑ D. Dubey, S. Ganesh: Modulation of functional properties of laforin phosphatase by alternative splicing reveals a novel mechanism for the EPM2A gene in Lafora progressive myoclonus epilepsy. In: Human Molecular Genetics . Volume 17, Number 19, October 2008, pp. 3010-3020, doi : 10.1093 / hmg / ddn199 , PMID 18617530 .
  6. ^ Matthew S. Gentry, Carlos Romá-Mateo, Pascual Sanz: Laforin, a protein with many faces: glucan phosphatase, adapter protein, et alii. In: FEBS Journal. 280, 2013, p. 525, doi : 10.1111 / j.1742-4658.2012.08549.x .
  7. ↑ C. Aguado, S. Sarkar, VI Korolchuk, O. Criado, S. Vernia, P. Boya, P. Sanz, SR de Córdoba, E. Knecht, DC Rubinsztein: Laforin, the most common protein mutated in Lafora disease, regulates autophagy. In: Human Molecular Genetics . Volume 19, number 14, July 2010, pp. 2867-2876, doi : 10.1093 / hmg / ddq190 , PMID 20453062 , PMC 2893813 (free full text).
  8. ↑ MS Gentry, C. Romá-Mateo, P. Sanz: Laforin, a protein with many faces: glucan phosphatase, adapter protein, et alii. In: The FEBS journal. Volume 280, number 2, January 2013, pp. 525-537, doi : 10.1111 / j.1742-4658.2012.08549.x , PMID 22364389 , PMC 3371293 (free full text).
  9. ↑ C. Roma Mateo, M. d. Solaz-Fuster, JV Gimeno-Alcañiz, VV Dukhande, J. Donderis, CA Worby, A. Marina, O. Criado, A. Koller, S. Rodriguez De Cordoba, MS Gentry, P. Sanz: Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase. In: The Biochemical journal. Volume 439, number 2, October 2011, pp. 265-275, doi : 10.1042 / BJ20110150 , PMID 21728993 , PMC 3299407 (free full text).
  10. ↑ Genetics Home Reference: Lafora progressive myoclonus epilepsy. Retrieved August 13, 2017 .