Linked Life Data

19765191

Source:http://linkedlifedata.com/resource/pubmed/id/19765191

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2009-10-23
pubmed:abstractText
The p62/sequestosome 1 protein has been identified as a component of pathological protein inclusions in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). P62 has also been implicated in autophagy, a process of mass degradation of intracellular proteins and organelles. Autophagy is a critical pathway for degrading misfolded and/or damaged proteins, including the copper-zinc superoxide dismutase (SOD1) mutants linked to familial ALS. We previously reported that p62 interacted with ALS mutants of SOD1 and that the ubiquitin-association domain of p62 was dispensable for the interaction. In this study, we identified two distinct regions of p62 that were essential to its binding to mutant SOD1: the N-terminal Phox and Bem1 (PB1) domain (residues 1-104) and a separate internal region (residues 178-224) termed here as SOD1 mutant interaction region (SMIR). The PB1 domain is required for appropriate oligomeric status of p62 and the SMIR is the actual region interacting with mutant SOD1. Within the SMIR, the conserved W184, H190 and positively charged R183, R186, K187, and K189 residues are critical to the p62-mutant SOD1 interaction as substitution of these residues with alanine resulted in significantly abolished binding. In addition, SMIR and the p62 sequence responsible for the interaction with LC3, a protein essential for autophagy activation, are independent of each other. In cells lacking p62, the existence of mutant SOD1 in acidic autolysosomes decreased, suggesting that p62 can function as an adaptor between mutant SOD1 and the autophagy machinery. This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy-lysosome degradation pathway.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1471-4159
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
111
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1062-73
pubmed:dateRevised
2011-8-1
pubmed:meshHeading
pubmed-meshheading:19765191-Adaptor Proteins, Signal Transducing, pubmed-meshheading:19765191-Animals, pubmed-meshheading:19765191-Cells, Cultured, pubmed-meshheading:19765191-Embryo, Mammalian, pubmed-meshheading:19765191-Heat-Shock Proteins, pubmed-meshheading:19765191-Humans, pubmed-meshheading:19765191-Immunoprecipitation, pubmed-meshheading:19765191-Mice, pubmed-meshheading:19765191-Mice, Inbred C57BL, pubmed-meshheading:19765191-Microtubule-Associated Proteins, pubmed-meshheading:19765191-Motor Neurons, pubmed-meshheading:19765191-Mutation, pubmed-meshheading:19765191-Protein Binding, pubmed-meshheading:19765191-Protein Structure, Tertiary, pubmed-meshheading:19765191-Spinal Cord, pubmed-meshheading:19765191-Superoxide Dismutase, pubmed-meshheading:19765191-Transfection, pubmed-meshheading:19765191-Ubiquitin
pubmed:year
2009
pubmed:articleTitle
Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism.
pubmed:affiliation
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural