Sandbox Reserved 1480

Function

The human protein LHPP or phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is part of the haloacid dehalogenase (HAD) family. It is a protein of 271 amino acids and is encoded by a seven exon gene positioned on the chromosome 10. LHPP has two domains, one catalytic domain with a magnesium ion (Mg2+) on the active site and a large C2a-type cap domain, and forms a homodimer in solution. Despite the large cap, the enzyme is not only able to act on small metabolites, but also on phosphoproteins. The protein is found in the nucleus and in the cytoplasm.

LHPP is a phosphatase with an in vitro activity towards inorganic pyrophosphate, imidodiphosphate, 3‑phosphohistidine and 6‑phospholysine. The enzyme acts more effectively on N-P bonds than O-P bonds. It binds 1 Mg2+ ion per subunit.

Fig 1. Simplified catalytic mechanism of HAD phosphatases. Asp acts as a nucleophile and Asp+2 as a acid/base. The phosphorylated substrate and the respective leaving groups are shown in red, and the water nucleophile is in blue. (Source: Do metabolic HAD phosphatases moonlight as protein phosphatases?, A. Gohla, 2018). In the human LHPP, the Asp+2 is replaced by a Serine.

Expressed in brain (highest expression level in C1 segment of cervical spinal cord), and at lower levels in liver and kidney.

Detected in thyroid at protein level.

Disease

Different studies have shown that LHPP is a risk factor in cancer and major depressive disorder.

It has also been shown that LHPP is a histidine phosphatase and a tumour suppressor in hepatocellular carcinoma that removes histidine-linked phosphate groups from proteins. The absence of LHPP promotes the growth of tumors via increasing histidine-phosphorylated proteins. This study shown that LHPP was downregulated in hepatocellular carcinoma, but also two histidine phosphatases (NME1 and NME2) were upregulated. Thus, the regulation of protein phosphorylation is important for the integrity of the cell and when deregulated could lead to tumorigenesis. They also shown that LHPP act mainly on N3-phosphorylated proteins.

The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.

Relevance

Structural highlights

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