PLSCR3 explained

Phospholipid scramblase 3 is an enzyme that in humans is encoded by the PLSCR3 gene^{[1] [2]} (abbreviated to PLS3 in this section). Like the other phospholipid scramblase family members (PLS1, PLS2, PLS4), PLS3 is a type II plasma membrane protein that is rich in proline and integral in apoptosis, or programmed cell death. The regulation of apoptosis is critical for both cell development and tissue homeostasis^[3]

Although phospholipid scramblase is thought to exist in all eukaryotic cells, PLS3 is a protein that is novel to the mitochondria.^[4] This is very important because mitochondria are central in the apoptotic cell pathway. This newly found member of the scramblase family is "responsible for phospholipid translocation between two lipid compartments," ^[3] the inner mitochondrial membrane and the outer membrane. Further experimental evidence suggests that the mechanism and effectors of PLS3's enzymatic activity are rather nuanced.

Effect on mitochondrial cardiolipin

Cardiolipin is a mitochondrion-specific phospholipid found in both the mitochondrial inner and outer membranes^[5] Many studies speculate that cardiolipin is a likely player in mitochondrial apoptosis. In a study done by R Lee et al., it was found that during apoptosis, cardiolipin in the outer membrane of the mitochondria increased from 10% to 30% saturation. Finding that cardiolipin concentration in the outer mitochondrial membrane increased during apoptosis (as well as knowing the function that PLS3 plays in mitochondrial apoptotic effects) clued Lee in to the fact that PLS3 may have effects on this cardiolipin membrane redistribution. Lee’s study looked into the consequences of cardiolipin redistribution in the mitochondria and found that cardiolipin plays a critical role in proteins that are involved with oxidative respiration (such as ATP synthase), which in turn affects ATP production. In Lee's experiment determining the effect of cardiolipin deprivation on cells, he studied an infected yeast mutant that lacked a cardiolipin creating enzyme, and found that although it was viable, the yeast was "moderately deficient in mitochondrial energy transforming machinery."

It was subsequently deduced that PLS3 is an effector for the redistribution of cardiolipin from the inner to outer mitochondrial membrane. Thus, when PLS3 flips cardiolipin across the inner to outer membrane of the mitochondria, the oxidative phosphorylation induced is greatly disturbed. It was deduced experimentally that a lack of proper oxidative phosphorylation is directly linked with mitochondrial apoptosis. Thus, this PLS3-induced redistribution of cardiolipin during apoptosis has major effects on mitochondrial function.

Summary

Although the results of the experiments above are very intriguing and shed light on what was once a mystery, there have been only a few experiments that have targeted PSL3. And, furthermore, in a majority of the experiments and studies that were reviewed, it is evident that there is some doubt in the experimental findings ^{[6] [7] [8]}

See also

• Scramblase

Further reading

• He Y, Liu J, Grossman D, Durrant D, Sweatman T, Lothstein L, Epand RF, Epand RM, Lee RM . Phosphorylation of mitochondrial phospholipid scramblase 3 by protein kinase C-delta induces its activation and facilitates mitochondrial targeting of tBid . Journal of Cellular Biochemistry . 101 . 5 . 1210–21 . Aug 2007 . 17226776 . 10.1002/jcb.21243 . 10388586 .
• Van Q, Liu J, Lu B, Feingold KR, Shi Y, Lee RM, Hatch GM . Phospholipid scramblase-3 regulates cardiolipin de novo biosynthesis and its resynthesis in growing HeLa cells . The Biochemical Journal . 401 . 1 . 103–9 . Jan 2007 . 16939411 . 1698660 . 10.1042/BJ20060373 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Liu J, Dai Q, Chen J, Durrant D, Freeman A, Liu T, Grossman D, Lee RM . Phospholipid scramblase 3 controls mitochondrial structure, function, and apoptotic response . Molecular Cancer Research . 1 . 12 . 892–902 . Oct 2003 . 14573790 .
• Liu J, Chen J, Dai Q, Lee RM . Phospholipid scramblase 3 is the mitochondrial target of protein kinase C delta-induced apoptosis . Cancer Research . 63 . 6 . 1153–6 . Mar 2003 . 12649167 .

Notes and References

1. Wiedmer T, Zhou Q, Kwoh DY, Sims PJ . Identification of three new members of the phospholipid scramblase gene family . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1467 . 1 . 244–53 . Jul 2000 . 10930526 . 10.1016/S0005-2736(00)00236-4 . free .
2. Web site: Entrez Gene: PLSCR3 phospholipid scramblase 3.
3. Liu J, Dai Q, Chen J, Durrant D, Freeman A, Liu T, Grossman D, Lee RM . Phospholipid scramblase 3 controls mitochondrial structure, function, and apoptotic response . Molecular Cancer Research . 1 . 12 . 892–902 . Oct 2003 . 14573790 .
4. Wiedmer T, Zhou Q, Kwoh DY, Sims PJ . Identification of three new members of the phospholipid scramblase gene family . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1467 . 1 . 18240–4 . Jul 2000 . 10930526 . 10.1016/S0005-2736(00)00236-4. free .
5. US . 20060172958 . patent . Phospholipid scramblase 3 . 2006-08-03 . 2004-03-15 . 2004-03-13 . Ruey-min Lee . Qiang Dai . Jun Chen . Jihua Liu.
6. Pomorski T, Menon AK . Lipid flippases and their biological functions . Cellular and Molecular Life Sciences . 63 . 24 . 2908–21 . Dec 2006 . 17103115 . 10.1007/s00018-006-6167-7 . 25856483 . 11136118 .
7. Frasch SC, Henson PM, Kailey JM, Richter DA, Janes MS, Fadok VA, Bratton DL . Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase Cdelta . The Journal of Biological Chemistry . 275 . 30 . 23065–73 . Jul 2000 . 10770950 . 10.1074/jbc.M003116200 . free .
8. Sahu SK, Gummadi SN, Manoj N, Aradhyam GK . Phospholipid scramblases: an overview . Archives of Biochemistry and Biophysics . 462 . 1 . 103–14 . Jun 2007 . 17481571 . 10.1016/j.abb.2007.04.002 .