PAPSS2

Official Full Name

3'-phosphoadenosine 5'-phosphosulfate synthase 2

Organism

Homo sapiens

GeneID

9060

Background

Sulfation is a common modification of endogenous (lipids, proteins, and carbohydrates) and exogenous (xenobiotics and drugs) compounds. In mammals, the sulfate source is 3'-phosphoadenosine 5'-phosphosulfate (PAPS), created from ATP and inorganic sulfate. Two different tissue isoforms encoded by different genes synthesize PAPS. This gene encodes one of the two PAPS synthetases. Defects in this gene cause the Pakistani type of spondyloepimetaphyseal dysplasia. Two alternatively spliced transcript variants that encode different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

Synonyms

SK2; BCYM4; ATPSK2;

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Detailed Information

The osteoarthritis-associated gene PAPSS2 promotes differentiation and matrix formation in ATDC5 chondrogenic cells

For the important role of 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) in the development of normal skeletal structure, its involvement in the differentiation of chondrocytes as well as con-responding mechanisms has been evaluated in recent studies. PAPSS2 gene silence and overexpression in ATDC5 chondrogenic cells were performed by lentivirus and retrovirus mediated RNA interference. In ATDC5-induced chondrocyte-like cells during differentiation, the transcript expression levels of PAPSS2 progressively declined. Cell differentiation and decreased expression of collagen II and X can be significantly attenuated by silencing of PAPSS2 expression. And over-expression of PAPSS2 can counteract it. In the contrast between the PAPSS2 knockdown cells and control one, the mRNA expression levels of Wnt4 and SOX9 were found to be decreased significantly, and it was increased in the over-expressing PAPSS2 cells. Those findings underpinned the notion that differentiation in ATDC5 cells was induced by PAPSS2 via direct regulation on signaling events to promote the formation of collagenous matrix components.

PAPSS2 in patients and cellular environment

Due to the complexity and crowdedness of the environment within the cell, where might be existing an excluded-volume effects stabilization and quinary interactions with other proteins destabilization. As a dimeric and bifunctional enzyme, PAPS synthases can provide activated sulfate in the form of 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for sulfation reactions. PAPSS2 is a naturally fragile protein with a significant difference from PAPSS1 in its protein stability. Some bindings between the PAPS synthases and a series of nucleotide ligands can markedly stabilize these proteins. Several pathologies derived from the biomedical relevance of PAPS synthases as a destabilization point for mutations. Bone and cartilage malformations, as well as steroid sulfation defect, has some linkages with the genetic defects in PAPSS2. Intracellular aggregation and ubiquitination of PAPSS2 can be triggered by a subset of mutation induced severe PAPSS2 protein destabilization. All these candidates PAPS synthases as targets to study protein unfolding, ligand binding, and the stabilizing and destabilizing factors in their cellular environment. Linkages between the current concepts of protein folding or stability and understanding of the different disease mechanisms of PAPSS2-related pathologies may put forward more insights for future research and application.

Figure 1. Hypothetical influence of PAPSS2 gene in PSA recurrence. (Shibo Ying, et al. 2015)

References:

Ibeawuchi C, Schmidt H, Voss R, et al. Exploring prostate cancer genome reveals simultaneous losses of PTEN, FAS and PAPSS2 in patients with PSA recurrence after radical prostatectomy. International journal of molecular sciences, 2015, 16(2): 3856-3869.
Fan L, He Y, Han J, et al. The osteoarthritisassociated gene PAPSS2 promotes differentiation and matrix formation in ATDC5 chondrogenic cells. Experimental and Therapeutic Medicine, 2018, 16(6): 5190-5200.
Brylski O, Ebbinghaus S, Mueller J W. Melting down protein stability: PAPS synthase 2 in patients and in a cellular environment. Frontiers in Molecular Biosciences, 2019, 6: 31.

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