GPS-PAIL: prediction of lysine acetyltransferase-specific modification sites from protein sequences

Abstract

Protein acetylation catalyzed by specific histone acetyltransferases (HATs) is an essential posttranslational modification (PTM) and involved in the regulation a broad spectrum of biological processes in eukaryotes. Although several ten thousands of acetylation sites have been experimentally identified, the upstream HATs for most of the sites are unclear. Thus, the identification of HAT-specific acetylation sites is fundamental for understanding the regulatory mechanisms of protein acetylation. In this work, we first collected 702 known HAT-specific acetylation sites of 205 proteins from the literature and public data resources, and a motif-based analysis demonstrated that different types of HATs exhibit similar but considerably distinct sequence preferences for substrate recognition. Using 544 human HAT-specific sites for training, we constructed a highly useful tool of GPS-PAIL for the prediction of HAT-specific sites for up to seven HATs, including CREBBP, EP300, HAT1, KAT2A, KAT2B, KAT5 and KAT8. The prediction accuracy of GPS-PAIL was critically evaluated, with a satisfying performance. Using GPS-PAIL, we also performed a large-scale prediction of potential HATs for known acetylation sites identified from highthroughput experiments in nine eukaryotes. Both online service and local packages were implemented, and GPS-PAIL is freely available at: http://pail.biocuckoo.org.As one of the most important and ubiquitous post-translational modifications (PTMs) in proteins, the lysine acetylation catalyzed by histone acetyltransferases (HATs) or lysine acetyltransferases (KATs) reversibly regulates a large number of biological processes, such as transcriptional regulation, metabolism and autophagy [1][2][3][4][5][6][7] . The dysregulation of site-specific HAT-substrate relations is frequently associated with human diseases such as cancers 2,3,8,9 . In eukaryotes, numerous HATs have been classified into three major families including p300/CBP, GCN5-related N-acetyltransferases (GNATs) and MYST proteins 1-3,10,11 . Different HATs can recognize overlapping but distinct substrates 1,11,12 . Most HATs exist in multisubunit complexes in vivo by physically interacting with non-catalytic proteins, which are also involved in recognizing substrates and synergistically determine the specificity together with HATs 2,3 . In this regard, the identification of HAT-specific acetylation sites in proteins is fundamental for understanding the molecular mechanisms and regulatory roles of lysine acetylation.Previously, systematic identification of protein acetylation sites or "acetylome" was a great challenge, due to the technical limitation 4,13 . For example, in 2006, Kim et al. used

Molecular mechanisms of regulation of sphingosine kinase 1

“…It was also implicated in this work that acetylation of SK1 was able to affect SK1s ability to become ubiquitinated [45]. Using GPS-PAIL [46], a web-based predictor of protein acetylation, we were able to predict several residues which might be acetylated, including Lys29 (Table 1). However, this work needs to be verified and corroborated and much more research is needed to understand the mechanisms which induce SK1 acetylation and how acetylation might regulate SK1.…”

Hat1-Dependent Lysine Acetylation Targets Diverse Cellular Functions

“…Mitochondrial protein acetylation increases in mouse liver during fasting, caloric restriction or a long-term high fat diet (12,75,76), indicating that the acetylation patterns in this organelle can respond to dietary changes. Interestingly, mitochondrial proteins are also enriched in the Hat1-dependent acetylome ( Figure 5A).…”

“…Histone acetyltransferase 1 (Hat1) was the first protein ε-amino group lysine acetyltransferase to be identified and is the most widely conserved among eukaryotes (10)(11)(12). Like most lysine acetyltransferases, Hat1 was identified based on its ability to acetylate histones.…”

Acetylation‐mediated Siah2 stabilization enhances PHD3 degradation in Helicobacter pylori‐infected gastric epithelial cancer cells

“…2C). Acetylation of Siah2 was predicted using the GPS-PAIL tool (34). Among the predicted K residues with high probability for acetylation, K 129 and K 139 belong to the substrate-binding domain of Siah2.…”