Tafazzin

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SpeciesHumanMouse
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Tafazzin
Identifiers
SymbolTAZ
InterProIPR000872
Membranome459

Tafazzin is a protein that in humans is encoded by the TAZ gene.[1] Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid-lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acyltransferases).[2][3] It catalyzes remodeling of immature cardiolipin to its mature composition containing a predominance of tetralinoleoyl moieties.[4] Several different isoforms of the tafazzin protein are produced from the TAZ gene. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane-bound. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. Most isoforms are found in all tissues, but some are found only in certain types of cells.[5][1] Mutations in the TAZ gene have been associated with mitochondrial deficiency, Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, left ventricular noncompaction (LVNC), breast cancer, papillary thyroid carcinoma, non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.[1][6][7][8]

Structure

The TAZ gene is located on the q arm of chromosome X at position 28 and it spans 10,208 base pairs.[1] The TAZ gene produces a 21.3 kDa protein composed of 184 amino acids.[9][10] The structure of the encoded protein has been found to differ at their N terminus and the central region, which are two functionally notable regions. A 30 residue hydrophobic stretch at the N terminus may function as a membrane anchor, which does not exist in the shortest forms of tafazzins. The second region is a variable exposed loop located between amino acids 124 and 195 in the central region. This hydrophilic region is known to interact with other proteins. TAZ has no known resemblance to other proteins.[11]

Tafazzin is encoded by the TAZ gene. It is very unfortunate that a protein called TAZ (a 50kDA protein) which is a part of the Hippo/YAP/TAZ pathway gets confused with Tafazzin due to this misnaming often.

Tafazzin has at least 4 different isoforms. It has a molecular weight around 35kDa but may also appear in lower molecular weights due to species differences in isoform expression.

Function

The TAZ gene provides instructions for producing a protein called tafazzin, which is located in structures called mitochondria, which are the energy-producing centers of cells. Tafazzin is involved in altering a fat (lipid) called cardiolipin (CL), which plays critical roles in the mitochondrial inner membrane.[5]

Transacylase (remodeling)

After its synthesis, cardiolipin cannot exert its proper functions until it is actively remodeled. The remodeling process of cardiolipin involves reaching a final acyl composition. TAZ interacts with an immature cardiolipin by adding a fatty acid called linoleic acid, which catalyzes the remodeling of the cardiolipin. The remodeling is achieved by transacylation or the deacylation-reacylation cycle. The deacylation-reacylation cycle, also known as the Lands cycle begins with a deacylation mediated by a phospholipase and ends which forms monolyso-CL (MLCL). The cycle ends with a CoA-dependent reacylation. In contrast, transacylation involves the transfer of a linoleic acid (LA) group from phosphatidylcholine (PC) to MLCL. Such enzymatic activity forms lyso-PC and CL, and enriches the specific acyl chain of cardiolipin. The process has been shown to be specific for linoleoyl-containing PC. Such remodeling processes converts cardiolipin into a mature composition that contains a predominance of tetralinoleoyl moieties. The process enables the proper function of cardiolipin.[4][5][12]

Cardiolipin in mitochondrial structure and function

Cardiolipin is a complex glycerophospholipid which contains 4 acyl groups linked to three glycerol moietie localized in the mitochondrial inner membrane. These acyl groups include oleic acid and linoleic acid. Due to this composition, cardiolipin exhibits a conical structure, which allows for membrane curvature called cristae. Such qualities allow CL to play essential roles in maintaining mitochondrial shape, energy production, and protein transport within cells.[5] During apoptosis and similar processes, CL is known to act as a platform for proteins and other machinery involved.

Influence of cardiolipin on the respiratory chain

Cardiolipin has been shown to assist in energy production of the mitochondria. Several proteins in the mitochondrial respiratory chain require CL for optimal function.[13] CL has been found to be involved in the stabilization of each respiratory chain complex, enabling efficient electron transport.[14] CL assists in forming super-complexes with proteins localized in the inner mitochondrial matrix, which include the ATP/ADP translocase, pyruvate carrier, carnitine carrier, and all of the respiratory chain complexes (I, III,IV, V).[15][16] CL also enables trapping of protons in the intermembrane space, aiding ATP synthase to carry out its function of channeling protons into the mitochondrial matrix.[12]


Clinical significance

Mutations in the TAZ gene have been associated with a number of mitochondrial deficiencies and associated disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC).[1] TAZ has also been associated with various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.[6][7][8]

Barth Syndrome

Barth syndrome is an X-linked disease caused by mutations in the TAZ gene.[17][18] More than 160 mutations in the TAZ gene have been found to this disease. It is a rare condition that occurs almost exclusively in males. TAZ gene mutations that cause barth syndrome result in the production of tafazzin proteins with little or no function. As a result, linoleic acid is not added to cardiolipin, which causes problems with normal mitochondrial shape and functions such as energy production and protein transport. Tissues with high energy demands, such as the heart and other muscles, are most susceptible to cell death due to reduced energy production in mitochondria. Additionally, affected white blood cells have abnormally shaped mitochondria, which could impair their ability to grow (proliferate) and mature (differentiate), leading to a weakened immune system and recurrent infections. Dysfunctional mitochondria likely lead to other signs and symptoms of Barth syndrome.[5]

Common clinical manifestations include:[5][17][18]

Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.[17][18]

A c.348C>T mutation resulted in dilated cardiomyopathy with noncompaction of the ventricular myocardium.[19] A frame shift mutation of c.227delC displayed symptoms of neutropenia, cardiomegaly, and other common symptoms of Bath Syndrome.[20] Another a c.C153G mutation resulted in severe metabolic acidosis, cardiomegaly, and other major symptoms of Barth syndrome.[21]

In conclusion, tafazzin is responsible for remodeling of a phospholipid cardiolipin (CL),[22] the signature lipid of the mitochondrial inner membrane. Therefore, a dysfunctioning tafazzin has been found to lead to an impaired mitochondrial respiratory chain. As a result, Barth syndrome patients exhibit defects in cardiolipin metabolism, including aberrant cardiolipin fatty acyl composition, accumulation of monolysocardiolipin (MLCL) and reduced total cardiolipin levels.[23][24] This may lead to acute metabolic decompensation and sudden death. Cardiac transplantation is the only possibility at the present time.[21]

Dilated cardiomyopathy (DCM)

Some mutations in the TAZ gene cause dilated cardiomyopathy without the other features of Barth syndrome. Dilated cardiomyopathy is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently, often resulting in heart failure. The decreased blood flow can lead to swelling in the legs and abdomen, fluid in the lungs, and an increased risk of blood clots.[5]

Isolated noncompaction of left ventricular myocardium (INVM)

Mutations in the TAZ gene can cause a heart condition called isolated noncompaction of left ventricular myocardium (INVM). This condition occurs when the lower left chamber of the heart (left ventricle) does not develop correctly. In INVM, the heart muscle is weakened and cannot pump blood efficiently. Abnormal heart rhythms (arrhythmias) can also occur. INVM frequently causes heart failure.[5]

Cancer

Highly elevated TAZ activity has been linked to tumorigenesis and oncogenic activity. It has also been associated with and various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, and glioma.[6] In breast cancer, TAZ has been shown to be required for cancer cells to sustain self-renewal and create tumors.[25] Additionally, TAZ has been found to be highly expressed in gastric cancer cells resistant to cisplatin. This resistance was identified to be due to the acquired ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT). The findings that TAZ is involved in inducing EMT as well as its high levels in these cancer cells may point to its involvement in gastric cancer.[6][7] High expression of TAZ was also found in rectal cancer and thyroid neoplasms, indicating that TAZ may promote tumorigenesis and inhibit apoptosis.[8] In a study of 140 Swedish rectal cancer patients, high levels of TAZ was linked to rectal cancer development. Additionally, the levels of TAZ were connected to the radiotherapy response of the patients, potentially offering insight into cancer recurrence in patients.[26] A potential link between PI3K and TAZ indicates a possible association between PI3K signaling and TAZ as both were highly elevated in PTEN mutant cancer cells.[6]

Interactions

TAZ has been shown to have protein-protein interactions with the following and more.[27][17]


History

The protein was identified by Italian scientists Silvia Bione et al. in 1996.[11] Owing to the complex procedure required for the identification of tafazzin, the protein was named after "Tafazzi", a masochistic comic character in an Italian television show.

References

  1. 1.0 1.1 1.2 1.3 1.4 "Entrez Gene: tafazzin". This article incorporates text from this source, which is in the public domain.
  2. Xu Y, Zhang S, Malhotra A, Edelman-Novemsky I, Ma J, Kruppa A, Cernicica C, Blais S, Neubert TA, Ren M, Schlame M (October 2009). "Characterization of tafazzin splice variants from humans and fruit flies". The Journal of Biological Chemistry. 284 (42): 29230–9. doi:10.1074/jbc.M109.016642. PMC 2781466. PMID 19700766.
  3. Xu Y, Malhotra A, Ren M, Schlame M (December 2006). "The enzymatic function of tafazzin". The Journal of Biological Chemistry. 281 (51): 39217–24. doi:10.1074/jbc.M606100200. PMID 17082194.
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Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.