Abstract
Within the crowded and complex environment of the cell, a protein experiences stabilizing excluded-volume effects and destabilizing quinary interactions with other proteins. Which of these prevail, needs to be determined on a case-by-case basis. PAPS synthases are dimeric and bifunctional enzymes, providing activated sulfate in the form of 3′-phosphoadenosine-5′-phosphosulfate (PAPS) for sulfation reactions. The human PAPS synthases PAPSS1 and PAPSS2 differ significantly in their protein stability as PAPSS2 is a naturally fragile protein. PAPS synthases bind a series of nucleotide ligands and some of them markedly stabilize these proteins. PAPS synthases are of biomedical relevance as destabilizing point mutations give rise to several pathologies. Genetic defects in PAPSS2 have been linked to bone and cartilage malformations as well as a steroid sulfation defect. All this makes PAPS synthases ideal to study protein unfolding, ligand binding, and the stabilizing and destabilizing factors in their cellular environment. This review provides an overview on current concepts of protein folding and stability and links this with our current understanding of the different disease mechanisms of PAPSS2-related pathologies with perspectives for future research and application.
Highlights
Sulfation pathways are centered around enzymatic conversion of sulfate to the activated sulfate donor 3′-phosphoadenosine-5′-phosphosulfate (PAPS) and the transfer of the sulfuryl moiety to biological acceptor molecules (Foster and Mueller, 2018)
Considering changing ATP levels and PAPS synthase stabilization via ligand binding, we propose that the PAPSS2-ADP-APS complex within the APS kinase domain represents a stable storage form of the enzyme, and for the APS nucleotide, of relevance in times in which ATP levels are depleted
Activated sulfate in form of PAPS is essential for driving sulfation pathways inside cells
Summary
Sulfation pathways are centered around enzymatic conversion of sulfate to the activated sulfate donor 3′-phosphoadenosine-5′-phosphosulfate (PAPS) and the transfer of the sulfuryl moiety to biological acceptor molecules (Foster and Mueller, 2018). Sulfation impacts on many different acceptor molecules, such as carbohydrates, proteins, lipids, xenobiotics, and steroids as well as other hormones (Mueller et al, 2015) Several proteins from this pathway have been studied with regard to their stability; some of them giving rise to clinically observed pathologies (Oostdijk et al, 2015). PAPS synthases are bifunctional enzymes comprising a C-terminal ATP sulfurylase and an Nterminal APS kinase domain (Mueller and Shafqat, 2013) Their physiological substrates and products are sulfate, ATP, ADP, pyrophosphate, PAPS, and the reaction intermediate adenosine5′-phosphosulfate (APS) (Strott, 2002). This review will look at sulfation pathways, central to healthy human physiology from a protein-stability/protein-folding perspective
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