Protein post-translational modifications (PTMs) at the lysine residue, such as lysine methylation, acetylation, and ubiquitination, are diverse, abundant, and dynamic. They play a key role in the regulation of diverse cellular physiology. Here we report discovery of a new type of lysine PTM, lysine malonylation (Kmal). Kmal was initially detected by mass spectrometry and protein sequence-database searching. The modification was comprehensively validated by Western blot, tandem MS, and high-performance liquid chromatography of synthetic peptides, isotopic labeling, and identification of multiple Kmal substrate proteins. Kmal is a dynamic and evolutionarily conserved PTM observed in mammalian cells and bacterial cells. In addition, we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo. This result suggests the possibility of nondeacetylation activity of other class III lysine deacetylases, especially those without obvious acetylation protein substrates. Our results therefore reveal a new type of PTM pathway and identify the first enzyme that can regulate lysine malonylation and lysine succinylation status. Molecular & Cellular Proteomics 10: 10.1074/ mcp.M111.012658, 1-12, 2011.Cellular function and physiology are largely determined by the inventory of all proteins in a cell, its proteome. The collection and characterization of the proteome is critical to understanding cellular mechanisms and diseases. Proteomes in eukaryotic cells consist of over a million molecular species of proteins, easily orders of magnitude more complex than the corresponding genomes (1, 2). There are two major mechanisms for expanding the coding capacity of the human genome: mRNA splicing and protein post-translational modifications (PTMs)1 . PTMs (more than 300 types) are complex and fundamental mechanisms of cellular regulation, and have been associated with almost all known cellular pathways and disease processes (1, 2). As an example, protein phosphorylation, the most well-studied PTM, is present in more than one third of human proteins, the phosphorylation status of which can potentially be regulated by ϳ500 human protein kinases and ϳ150 phosphatases (3, 4). The modification mainly occurs at several amino acid residues: serine, threonine, tyrosine, and histidine. Protein phosphorylation makes its substrate residues more acidic, hydrophilic, and induces a charge change from ϩ1 charge to -1 (at physiological pH), which in turn modulates the structure and functions of substrate proteins.The high complexity of PTMs is also reflected by diverse modifications at -amine group of lysine residue, including methylation, acetylation, and ubiquitination. These lysine PTMs have been shown to play an important role in cellular regulations (5, 6). Recently, we identified a new type of PTM at lysine residues, lysine succinylation (7). Like phosporylation, lysine succinylation also induces a change of two negative charges in lysine re...

BackgroundTophi contribute to musculoskeletal disability, joint damage and poor health-related quality of life in people with gout. The aim of this study was to examine the role of SLC2A9 and ABCG2 variants in tophaceous disease in people with gout.MethodsParticipants (n = 1778) with gout fulfilling the 1977 American Rheumatism Association (ARA) classification criteria, who were recruited from primary and secondary care, attended a detailed study visit. The presence of palpable tophi was recorded. SLC2A9 rs11942223, ABCG2 rs2231142 and ABCG2 rs10011796 were genotyped. Data were analysed according to tophus status.ResultsCompared to participants without tophi, those with tophi were older, had longer disease duration and higher serum creatinine, and were more likely to be of Māori or Pacific (Polynesian) ancestry. SLC2A9 rs11942223 was not associated with tophi. However, the risk alleles for both ABCG2 single nucleotide polymorphisms (SNPs) were present more frequently in those with tophi (OR (95% CI) 1.24 (1.02–1.51) for rs2231142 and 1.33 (1.01–1.74) for rs10011796, p < 0.05 for both). The effect of rs2231142 was limited to participants of Māori or Pacific ancestry (OR 1.50 (1.14–1.99), p = 0.004), with a significant effect observed in those of Western Polynesian ancestry only (OR 1.71 (1.07–2.72), p = 0.017). The rs10011796 risk allele was strongly associated with tophi in the Western Polynesian group (OR 3.76 (1.61–8.77), p = 0.002), but not in the Eastern Polynesian group (OR 0.87 (0.52–1.46), p = 0.60) nor in the non-Polynesian group (OR 1.16 (0.81–1.66), p = 0.32). The ABCG2 associations persisted in the Western Polynesian group after adjusting for serum urate, creatinine, and disease duration, and when including both ABCG2 variants in the regression models.ConclusionsVariation in ABCG2 function may play a role in the development of tophaceous disease in some populations with high prevalence of severe gout.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1254-8) contains supplementary material, which is available to authorized users.

No abstract

In this paper, the effect of fiber dimensional irregularities on the tensile behavior of fiber bundles is modeled, using the finite element method (FEM). Fiber dimensional irregularities are simulated with sine waves of different magnitude. The specific stress-strain curves of fiber bundles and the constituent single fibers are obtained and compared. The results indicate that fiber diameter irregularity along fiber length has a significant effect on the tensile behavior of the fiber bundle. For a bundle of uniform fibers of different diameters, all constituent fibers will break simultaneously regardless of the fiber diameter. Similarly, if fibers within a bundle have the same pattern and level of diameter irregularity along fiber length, the fibers will break at the same time also regardless of the difference in average diameter of each fiber. In these cases, the specific stress and strain curve for the bundle overlaps with that of the constituent fibers. When the fiber bundle consists of single fibers with different levels of diameter irregularity, the specific stress-strain and load-elongation curves of the fiber bundle exhibit a stepped or "ladder" shape. The fiber with the highest irregularity breaks first, even when the thinnest section of the fiber is still coarser than the diameter of a very thin but uniform fiber in the bundle. This study suggests that fiber diameter irregularity along fiber length is a more important factor than the fiber diameter itself in determining the tensile behavior of a fiber bundle consisting of irregular fibers.

Most fibers are irregular and are often subjected to rapid straining during mechanical processing and end-use applications. In this article, the effect of fiber dimensional irregularities on the dynamic tensile behavior of irregular fibers was examined using the finite-element method (FEM). Fiber dimensional irregularities are simulated with sine waves of different magnitude (10, 30, and 50% level of diameter variation). The tensile behavior of irregular fibers was examined at different strain rates (333, 3333, and 30,000%/s). The breaking load and breaking extension of irregular fibers at different strain rates were then calculated from the finite-element model. The results indicate that strain rate has a significant effect on the dynamic tensile behavior of an irregular fiber, and that the position of the thinnest segment along the fiber significantly affects the simulation results. Under dynamic conditions, an irregular fiber does not necessarily break at the thinnest segment, which is different from the quasi-static results.