Structural Research of Membrane-Integral Pyrophosphatases (M-PPases)
Membrane-integral pyrophosphatases (M-PPases) hydrolyze pyrophosphate in living organisms and use pyrophosphate as an energy source for sodium or proton pumping. The study of the M-PPases catalytic cycle is of great help to improve or hinder protein function. M-PPases play an important role in plant maturation and abiotic stress tolerance. Can be modified to improve plant survival. M-PPases are also a selective drug target that can be studied to reduce the virulence of common pathogens.
Research Progress on the Structure of M-PPases
In the past few years, there have been structural and functional data of M-PPases indicating the mechanism involving half-of-the-sites reactivity, exit channel motions and inter-subunit communication. M-PPases have a single transmembrane domain with 15-17 transmembrane (TM) helices. The helix forms two concentric rings around the four catalytic regions. There is a large hydrophilic region on the cytoplasmic side of the protein that extends into the cytoplasm about 20 Å.
By studying the structure of the M-PPases, the complete catalytic cycle of proton and sodium pumps can be understood, and the specificity of ion transport across membranes can also be explained. Further study on the structure of M-PPases by X-ray diffraction to understand the mechanism of their catalytic pathway.
Figure 1. Structural features of M-PPases. (Holmes AOM et al., 2019)
| Protein | Organism | Method | Resolution | PDB Entry ID |
| Proton-Pumping Pyrophosphatase | Vigna radiata var. radiata | X-ray diffraction | 3.50 Å | 5GPJ |
| Sodium pumping membrane integral pyrophosphatase in complex with imidodiphosphate and magnesium, and with bound sodium ion | Thermotoga maritima MSB8 | X-ray diffraction | 2.495 Å | 5LZQ |
| Thermotoga maritima sodium pumping membrane integral pyrophosphatase in complex with tungstate and magnesium | Thermotoga maritima MSB8 | X-ray diffraction | 4.00 Å | 5LZR |
| Thermotoga Maritima sodium pumping membrane integral pyrophosphatase with metal ions in active site | Thermotoga maritima | X-ray diffraction | 2.60 Å | 4AV3 |
| Membrane bound pyrophosphatase in complex with imidodiphosphate and N-[(2-amino-6-benzothiazolyl) methyl]-1H-indole-2-carboxamide (ATC) | Thermotoga maritima MSB8 | X-ray diffraction | 3.41 Å | 6QXA |
| H-Translocating Pyrophosphatase | Vigna radiata | X-ray diffraction | 2.35 Å | 4A01 |
| Proton pyrophosphatase - two phosphates-bound | Vigna radiata var. radiata | X-ray diffraction | 3.299 Å | 6AFS |
| Proton pyrophosphatase - E301Q | Vigna radiata var. radiata | X-ray diffraction | 2.492 Å | 6AFT |
| Proton pyrophosphatase-L555M mutant | Vigna radiata var. radiata | X-ray diffraction | 2.15 Å | 6AFU |
| Proton pyrophosphatase-L555K mutant | Vigna radiata var. radiata | X-ray diffraction | 2.701 Å | 6AFV |
| Proton pyrophosphatase-T228D mutant | Vigna radiata var. radiata | X-ray diffraction | 2.185 Å | 6AFW |
| Proton pyrophosphatase - E225A | Vigna radiata var. radiata | X-ray diffraction | 2.301 Å | 6AFX |
| Proton pyrophosphatase-E225S mutant | Vigna radiata var. radiata | X-ray diffraction | 2.401 Å | 6AFY |
| Proton pyrophosphatase-E225H mutant | Vigna radiata var. radiata | X-ray diffraction | 2.483 Å | 6AFZ |
Table 1. Structural research of membrane-integral pyrophosphatases (M-PPases).
In recent years, an increasing number of M-PPases structures have been analyzed by X-ray crystallography. To explore its important role in plant maturation and abiotic stress. As well as pharmacological modulation through structural studies to reduce common pathogen virulence.
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References
- Kajander T, et al. Inorganic pyrophosphatases: one substrate, three mechanisms. FEBS Letters. 201, 587(13):1863-1869.
- Holmes AOM et al. The Function of Membrane Integral Pyrophosphatases From Whole Organism to Single Molecule. Frontiers in Molecular Biosciences. 2019; 6:132.
- Kellosalo J, et al. Crystallization and preliminary X-ray analysis of membrane-bound pyrophosphatases. Mol Membr Biol. 2013, 30(1):64-74.
