Abstract
Tyrosine sulfation is a type of post-translational modification (PTM) catalyzed by tyrosylprotein sulfotransferases (TPST). The modification plays a crucial role in mediating protein-protein interactions in many biologically important processes. There is no well-defined sequence motif for TPST sulfation, and the underlying determinants of TPST sulfation specificity remains elusive. Here, we perform molecular modeling to uncover the structural and energetic determinants of TPST sulfation specificity. We estimate the binding affinities between TPST and peptides around tyrosines of both sulfated and non-sulfated proteins to differentiate them. We find that better differentiation is achieved after including energy costs associated with local unfolding of the tyrosine-containing peptide in a host protein, which depends on both the peptide's secondary structures and solvent accessibility. Local unfolding renders buried peptide-with ordered structures-thermodynamically available for TPST binding. Our results suggest that both thermodynamic availability of the peptide and its binding affinity to the enzyme are important for TPST sulfation specificity, and their interplay results into great variations in sequences and structures of sulfated peptides. We expect our method to be useful in predicting potential sulfation sites and transferable to other TPST variants. Our study may also shed light on other PTM systems without well-defined sequence and structural specificities. All the data and scripts used in the work are available at http://dlab.clemson.edu/research/Sulfation.
Highlights
After their synthesis in the ribosome, many proteins undergo post-translational modifications (PTM) such as glycosylation, phosphorylation and peptide hydrolysis before reaching their fully functional forms
Tyrosine sulfation is a common PTM occurring on many proteins that transit through the Golgi apparatus, such as extracellular matrix proteins, serine protease inhibitors and G-protein coupled receptors (Stone et al, 2009)
The TPSP-2 enzyme has an N-terminal cytoplasmic domain, a transmembrane domain anchoring the protein in the Golgi membrane, a putative stem region and a luminal domain that catalyzes the tyrosine sulfation (Teramoto et al, 2013)
Summary
After their synthesis in the ribosome, many proteins undergo post-translational modifications (PTM) such as glycosylation, phosphorylation and peptide hydrolysis before reaching their fully functional forms. The SVM algorithm has been applied in another predictor based on predicted secondary structures and solvent accessible surface area (Chang et al, 2009) These statistics-based tools work satisfactorily in their test cases and have been useful in experimental studies of protein sulfation (Goff et al, 2003; Keykhosravani et al, 2005). Our study suggests that both the thermodynamics accessibility of a peptide and its binding affinity to TPST are important for sulfation The interplay of these two factors allows a great variety in sequences and structures of sulfated peptides, where a buried peptide with well-defined secondary structure might be sulfated if the peptide undergoes local unfolding, making itself available for enzyme binding
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