TY - JOUR
T1 - Insights into Lafora disease
T2 - Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin
AU - Gentry, Matthew S.
AU - Worby, Carolyn A.
AU - Dixon, Jack E.
PY - 2005/6/14
Y1 - 2005/6/14
N2 - Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy caused by recessive mutations in either a gene encoding a dual-specificity phosphatase, known as laforin, or a recently identified gene encoding the protein known as malin. Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. Missense mutations in malin that are present in LD patients abolish its ability to polyubiquitinate and signal the degradation of laforin. Our results demonstrate that laforin is a physiologic substrate of malin, and we propose possible models to explain how recessive mutations in either malin or laforin result in LD. Furthermore, these data distinguish malin as an E3 Ub ligase whose activity is necessary to prevent a neurodegenerative disease that involves formation of nonproteinacious inclusion bodies.
AB - Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy caused by recessive mutations in either a gene encoding a dual-specificity phosphatase, known as laforin, or a recently identified gene encoding the protein known as malin. Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. Missense mutations in malin that are present in LD patients abolish its ability to polyubiquitinate and signal the degradation of laforin. Our results demonstrate that laforin is a physiologic substrate of malin, and we propose possible models to explain how recessive mutations in either malin or laforin result in LD. Furthermore, these data distinguish malin as an E3 Ub ligase whose activity is necessary to prevent a neurodegenerative disease that involves formation of nonproteinacious inclusion bodies.
KW - Neurodegenerative disease
KW - Phosphatase
KW - Progressive myoclonus epilepsy
UR - http://www.scopus.com/inward/record.url?scp=20844463813&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20844463813&partnerID=8YFLogxK
U2 - 10.1073/pnas.0503285102
DO - 10.1073/pnas.0503285102
M3 - Article
C2 - 15930137
AN - SCOPUS:20844463813
SN - 0027-8424
VL - 102
SP - 8501
EP - 8506
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -