title: A computational analysis of S-(2-succino)cysteine sites in proteins.
abstract: The adduction of fumaric acid to the sulfhydryl group of certain cysteine (Cys) residues in proteins via a Michael-like reaction leads to the formation of S-(2-succino)cysteine (2SC) sites. Although its role remains to be fully understood, this post-translational Cys modification (protein succination) has been implicated in the pathogenesis of diabetes/obesity and fumarate hydratase-related diseases. In this study, theoretical approaches to address sequence- and 3D-structure-based features possibly underlying the specificity of protein succination have been applied to perform the first analysis of the available data on the succinate proteome. A total of 182 succinated proteins, 205 modifiable, and 1750 non-modifiable sites have been examined. The rate of 2SC sites per protein ranged from 1 to 3, and the overall relative abundance of modifiable sites was 10.8%. Modifiable and non-modifiable sites were not distinguishable when the hydrophobicity of the Cys-flaking peptides, the acid dissociation constant value of the sulfhydryl groups, and the secondary structure of the Cys-containing segments were compared. By contrast, significant differences were determined when the accessibility of the sulphur atoms and the amino acid composition of the Cys-flaking peptides were analysed. Based on these findings, a sequence-based score function has been evaluated as a descriptor for Cys residues. In conclusion, our results indicate that modifiable and non-modifiable sites form heterogeneous subsets when features often discussed to describe Cys reactivity are examined. However, they also suggest that some differences exist, which may constitute the baseline for further investigations aimed at the development of predictive methods for 2SC sites in proteins.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy. Electronic address: gianluca.miglio@unito.it.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Miglio
authors.affiliation: Department of Mathematics and Statistics, University of Strathclyde, Glasgow, UK.
authors.forename: Alessandro Damiano
authors.initials: AD
authors.lastname: Sabatino
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Veglia
authors.affiliation: Dipartimento di Matematica "Giuseppe Peano", Università degli Studi di Torino, Turin, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Giraudo
authors.affiliation: Dipartimento di Informatica, Università degli Studi di Torino, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Beccuti
authors.affiliation: Dipartimento di Informatica, Università degli Studi di Torino, Turin, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cordero
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000235:genetics; D019295:Computational Biology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics; D005650:Fumarates / Q000737:chemistry; D006801:Humans; D008962:Models, Theoretical; D008968:Molecular Conformation; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D020543:Proteome; D020539:Sequence Analysis, Protein; D013386:Succinates / Q000737:chemistry
chemical_list: D000596:Amino Acids; D005650:Fumarates; D011506:Proteins; D020543:Proteome; C511650:S-(2-succinyl)cysteine; D013386:Succinates; C032005:fumaric acid; D003545:Cysteine
keywords: Cysteine reactivity; Fumaric acid; Protein succination; S-(2-succino)cysteine sites