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 (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.

By Northern blot analysis, LHPP is expressed in brain (highest expression level in C1 segment of cervical spinal cord), and at lower levels in liver and kidney.

Physiological LHPP substrates have not yet been reported. Although the subcellular localization of LHPP is unknown, the protein seems to interact with ATP synthase subunits, and may be involved in mitochondrial oxidative phosphorylation.

Disease

Different studies have shown that LHPP is a risk factor in major depressive disorder. Indeed, single nucleotide polymorphisms (SNPs) are linked with serotonin receptor 1A-1019C > G genotyp in two different populations. Enhanced expression of the HTR1A 1A-1019C > G autoreceptor is implicated in the reduction of serotonergic neurotransmission, which is considered to be one of the primary defects in depression, resulting in stress and vulnerability.

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 that two histidine kinases (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. Collectively, this study provides unprecedented hints on cellular functions of LHPP, and shows that LHPP inactivation together with high NME1/2 expression and - activity is a key tumorigenic event in hepatocellular carcinomas.

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

Liver cancer is the second leading cause of cancer causing the most deaths. Hepatocellular carcinoma (HCC) represents approximately 90% of primary liver cancer cases. In order to finally find a solution to this disease that is ravaging thousands of people, the discovery of the role of the LHPP protein as a suppressor tumor is essential to hopefully cure liver cancer patients by turning off the uncontrolled growth of cells.

Moreover, the mode of action of the protein could also be relevant for other cancers types.

Structural highlights

Full crystallographic information is available from OCA

Chemicals: 7 molecules: 2 Pyrophosphate (1), 2 Magnesium ion (2), 2 4-(2-hydroxyethyl)-1-Piperazine ethanesulfonic acid (3), 1 glycerol (4)

Proteins : 2 molecules (A,B)

Fig 2. Simplified structure of LHPP. 1: Pyrophosphate, 2: Magnesium ion, 3: 4-(2-hydroxyethyl)-1-Piperazine ethanesulfonic acid, 4: Glycerol. Source : Uniprot, 2018