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Proteomics techniques have revealed that lysine acetylation is abundant in mitochondrial proteins. This study was undertaken (1) to determine the relationship between mitochondrial protein acetylation and insulin sensitivity in human skeletal muscle, identifying key acetylated proteins, and (2) to use molecular modeling techniques to understand the functional consequences of acetylation of adenine nucleotide translocase 1 (ANT1), which we found to be abundantly acetylated. Eight lean and eight obese nondiabetic subjects had euglycemic clamps and muscle biopsies for isolation of mitochondrial proteins and proteomics analysis. A number of acetylated mitochondrial proteins were identified in muscle biopsies. Overall, acetylation of mitochondrial proteins was correlated with insulin action (r = 0.60; P < 0.05). Of the acetylated proteins, ANT1, which catalyzes ADP-ATP exchange across the inner mitochondrial membrane, was acetylated at lysines 10, 23, and 92. The extent of acetylation of lysine 23 decreased following exercise, depending on insulin sensitivity. Molecular dynamics modeling and ensemble docking simulations predicted the ADP binding site of ANT1 to be a pocket of positively charged residues, including lysine 23. Calculated ADP-ANT1 binding affinities were physiologically relevant and predicted substantial reductions in affinity upon acetylation of lysine 23. Insertion of these derived binding affinities as parameters into a complete mathematical description of ANT1 kinetics predicted marked reductions in adenine nucleotide flux resulting from acetylation of lysine 23. Therefore, acetylation of ANT1 could have dramatic physiological effects on ADP-ATP exchange. Dysregulation of acetylation of mitochondrial proteins such as ANT1 therefore could be related to changes in mitochondrial function that are associated with insulin resistance.
Pubmed ID: 24884163 RIS Download
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IPI provides a top level guide to the main databases (UniProtKB/Swiss-Prot, UniProtKB/TrEMBL, RefSeq, Ensembl, TAIR, H-InvDB, Vega) that describe the proteomes of higher eukaryotic organisms. IPI: :1. effectively maintains a database of cross references between the primary data sources :2. provides minimally redundant yet maximally complete sets of proteins for featured species (one sequence per transcript) :3. maintains stable identifiers (with incremental versioning) to allow the tracking of sequences in IPI between IPI releases. IPI is updated monthly in accordance with the latest data released by the primary data sources. As previously announced, the closure of IPI has been proposed for some time. Replacement data sets are now available through UniProt for human and mouse; sets for the other species contained within IPI are expected to be included as part of the UniProt release 2011_07. To allow users time to transition to using the new UniProt data sets, IPI releases will continue to be produced throughout the summer. The final release will be made in September 2011. Thereafter, the IPI website will cease to be maintained, although previous releases of the dataset will continue to be available from the FTP site. We would like to thank our users for their support and interest in this service.
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