Abstract
Conformational flexibility influence the binding of the substrate and the cofactor in TPST-2.
Highlights
In order to provide this missing but crucially important knowledge we performed a comprehensive atomistic molecular dynamics study which revealed that (i) the conformational flexibility influences sensitively key structural determinants and interactions between the enzyme, the substrate and the cofactor; (ii) a more open conformation adopted by the substrate for binding in tyrosylprotein sulfotransferase (TPST) 2; (iii) the mutations of key residues related with catalysis and binding change alter the enzyme structure and influence important interactions between the enzyme, the cofactor and the substrate
Tyrosine sulfated proteins are the product of post translational modi cation (PTM), where a sulfate group is covalently added to the hydroxyl group of tyrosine residues of the polypeptide chain.[1]
The simulations show that the sulfate group is stabilized by hydrogen bonds with S79, G80, T81 and T82, that the vast majority of interactions in the crystal structure are stable during the simulation and that there are two new hydrophobic interactions stabilizing the adenine ring
Summary
Tyrosine sulfated proteins are the product of post translational modi cation (PTM), where a sulfate group is covalently added to the hydroxyl group of tyrosine residues of the polypeptide chain.[1] The trans-Golgi networks in the cell harbor tyrosylprotein sulfotransferase (TPST) which is an enzyme responsible for the tyrosine sulfation reaction.[1,2] The tyrosine sulfation is very well characterized in eukaryotes and it has been predicted that up to 1% of tyrosine residues in the eukaryotic proteome have the potential to be sulfated.[3] Tyrosine sulfation plays a crucial role in protein–protein interactions in the extracellular environment and recently became increasingly important for biomedicine and as a target for drug design.[4,5,6,7,8] For example, the interaction of HIV's gp[120] protein with CCR5 in order to get entry to CD4+ T-lymphocytes requires sulfated tyrosine residues.[9] The enterovirus[71] virus responsible for neurological diseases in children depends on the tyrosine sulfation of PSGL1 on leukocytes in order to gain entry to cells and cause infection.[10] approximately sixty immune system proteins
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