Tafazzin

TAFAZZIN
Identifiers
Aliases	TAFAZZIN, BTHS, CMD3A, EFE, EFE2, G4.5, LVNCX, Taz1, tafazzin, TAZ, tafazzin, phospholipid-lysophospholipid transacylase
External IDs	OMIM: 300394 MGI: 109626 HomoloGene: 37264 GeneCards: TAFAZZIN
Gene location (Human) Chr. X chromosome (human) Band Xq28 Start 154,411,524 bp End 154,421,726 bp
Gene location (Mouse) Chr. X chromosome (mouse) Band X A7.3|X 37.95 cM Start 73,325,518 bp End 73,333,757 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of thyroid gland spleen left lobe of thyroid gland tibial nerve canal of the cervix right lung left ventricle upper lobe of left lung anterior pituitary gastric mucosa Top expressed in submandibular gland saccule lip skeletal muscle tissue parotid gland secondary oocyte extraocular muscle temporal muscle seminal vesicula digastric muscle More reference expression data BioGPS n/a
Gene ontology Molecular function acyltransferase activity 1-acylglycerophosphocholine O-acyltransferase activity 1-acylglycerol-3-phosphate O-acyltransferase activity O-acyltransferase activity Cellular component cytoplasm integral component of membrane cytosol mitochondrial membranes membrane mitochondrion mitochondrial inner membrane intrinsic component of membrane nucleus Biological process muscle contraction cardiac muscle contraction mitochondrial ATP synthesis coupled electron transport cardiac muscle tissue development cristae formation mitochondrial respiratory chain complex I assembly heart development cardiolipin biosynthetic process metabolism cardiolipin acyl-chain remodeling skeletal muscle tissue development phospholipid metabolic process positive regulation of cardiolipin metabolic process positive regulation of ATP biosynthetic process hemopoiesis inner mitochondrial membrane organization regulation of gene expression Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6901 66826 Ensembl ENSG00000102125 ENSMUSG00000009995 UniProt Q16635 Q91WF0 RefSeq (mRNA) NM_000116 NM_001303465 NM_181311 NM_181312 NM_181313 NM_181314 NM_001173547 NM_001242615 NM_001242616 NM_001290738 NM_181516 RefSeq (protein) NP_000107 NP_001290394 NP_851828 NP_851829 NP_851830 NP_001167018 NP_001229544 NP_001229545 NP_001277667 NP_852657 Location (UCSC) Chr X: 154.41 – 154.42 Mb Chr X: 73.33 – 73.33 Mb PubMed search
Wikidata
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Tafazzin
Identifiers
Symbol	TAZ
InterPro	IPR000872
Membranome	459

Tafazzin is a protein that in humans is encoded by the TAZ gene. Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid-lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acyltransferases). It catalyzes remodeling of immature cardiolipin to its mature composition containing a predominance of tetralinoleoyl moieties. 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. 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.

It is important to note that the TAZ gene is frequently confused with a protein called TAZ (transcriptional coactivator with PDZ-binding motif, a 50kDA protein). which is a part of the Hippo pathway and entirely unrelated to the gene of interest.

Structure

The TAZ gene is located on the q arm of chromosome X at position 28 and it spans 10,208 base pairs. The TAZ gene produces a 21.3 kDa protein composed of 184 amino acids. 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. The half-life of tafazzin is just 3-6 hours, considerably shorter than most mitochondrial proteins, which may explain research difficulties in studying its structure.

The putative phospholipid-binding site, which is the active site of Tafazzin, is a 57 amino acid cleft with two open ends and positively charged residues. In addition, tafazzin localizes to the membrane leaflets facing the intermembrane space (IMS), which is crucial for remodeling. Tafazzin differs from phospholipases in that it contains a conserved histidine residue, His-77, as part of the conserved HX4D motif seen in acyltransferases. This motif is responsible for facilitating the Asp-His dyad mechanism seen in many serine proteases. Many unique forms of tafazzin have been identified, with lengths from 129 to 292 amino acids. 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. 7 functional classes of TAZ mutations have been classified based on the pathogenic loss-of-function mechanisms of each mutation.

The TAZ gene contains two peptides independent of its active site for directing the protein to the mitochondria, forming residues 84-95 in exon 3 and residues 185-200 in exon 7/8 targets. Tafazzin localizes with peripheral association to membrane leaflets between the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM), facing the intermembrane space (IMS). Tafazzin’s characteristic interfacial anchoring is achieved by its hydrophobic sequence from residues 215-232. Finally, the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM) mediates tafazzin’s movement and insertion into the OMM and anchoring to IMM.

Function

The TAZ gene provides instructions for producing a protein called tafazzin, which is localized to mitochondria, the energy-producing centers of cells. Tafazzin transacylase activity is responsible for cardiolipin remodeling, critical to maintaining mitochondrial inner membrane structure and function. It also has unique acyl specificity and membrane curvature sensing capabilities.

Transacylase (remodeling)

After its synthesis, cardiolipin cannot exert its proper functions until it is actively remodeled. Tafazzin, an acyl-specific transferase, catalyzes the acyl transfer reaction between phospholipids and lysophospholipids in a CoA-independent manner. The remodeling process of cardiolipin involves reaching a final acyl composition that is primarily linoleoyl residues. TAZ interacts with an immature cardiolipin by adding the fatty acid 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 deacylation mediated by phospholipase Cld1 to form monolysocardiolipin (MLCL). MLCL is reacylated by tafazzin in a single-step reaction which transfers a linoleic acid group from phosphatidylcholine (PC), completing the CL deacylation-reacylation cycle. In contrast, transacylation involves the transfer of a linoleic acid 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. CL remodeling in mammals requires additional enzymes, such as monolysocardiolipin acyltransferase (MLCLAT), acyl-CoA:lysocardiolipin acyltransferase (ALCAT), and phospholipase. The process enables the proper function of cardiolipin.

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. 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. CL has been found to be involved in the stabilization of each respiratory chain complex, enabling efficient electron transport. 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). 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.

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). 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.

Barth Syndrome

Barth syndrome is an X-linked disease caused by mutations in the TAZ gene. 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.

Common clinical manifestations include:

• dilated cardiomyopathy (enlarged and weakened heart)
• muscle weakness
• recurrent infections
• short stature
• endocardial fibroelastosis
• growth retardation
• neutropenia
• organic aciduria (3-methylglutaconic acid)

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.

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

In conclusion, tafazzin is responsible for remodeling of a phospholipid cardiolipin (CL), 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. This may lead to acute metabolic decompensation and sudden death. Cardiac transplantation is the only possibility at the present time.

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.

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.

Cancer

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. High expression of TAZ was also found in rectal cancer and thyroid neoplasms, indicating that TAZ may promote tumorigenesis and inhibit apoptosis. 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. 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.

Interactions

TAZ has been shown to have protein-protein interactions with the following and more.

• FUT11
• BTRC
• NAGA
• NID2
• ANKRD46
• VWDE
• ITGA8

History

The protein was discovered in 1996 by Italian scientists Silvia Bione et al.. Owing to the complex procedure required for the identification of tafazzin, the protein was named after Tafazzi, an Italian comedy character who enthusiastically beats his groin with a plastic bottle.

Further reading

• "Mouse model of Barth syndrome". SciBX. 3 (47): 1427. Dec 9, 2010. doi:10.1038/scibx.2010.1427.
• Soustek MS, Falk DJ, Mah CS, Toth MJ, Schlame M, Lewin AS, Byrne BJ (July 2011). "Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency". Human Gene Therapy. 22 (7): 865–71. doi:10.1089/hum.2010.199. PMC 3166794. PMID 21091282.
• Takeda A, Sudo A, Yamada M, Yamazawa H, Izumi G, Nishino I, Ariga T (November 2011). "Barth syndrome diagnosed in the subclinical stage of heart failure based on the presence of lipid storage myopathy and isolated noncompaction of the ventricular myocardium". European Journal of Pediatrics. 170 (11): 1481–4. doi:10.1007/s00431-011-1576-5. PMID 21932011.
• Bachou T, Giannakopoulos A, Trapali C, Vazeou A, Kattamis A (2009). "A novel mutation in the G4.5 (TAZ) gene in a Greek patient with Barth syndrome". Blood Cells, Molecules & Diseases. 42 (3): 262–4. doi:10.1016/j.bcmd.2008.11.004. PMID 19261493.
• Gonzalez IL (May 2005). "Barth syndrome: TAZ gene mutations, mRNAs, and evolution". American Journal of Medical Genetics Part A. 134 (4): 409–14. doi:10.1002/ajmg.a.30661. PMID 15793838.
• Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (September 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. PMID 16169070.
• Zimmerman RS, Cox S, Lakdawala NK, Cirino A, Mancini-DiNardo D, Clark E, Leon A, Duffy E, White E, Baxter S, Alaamery M, Farwell L, Weiss S, Seidman CE, Seidman JG, Ho CY, Rehm HL, Funke BH (May 2010). "A novel custom resequencing array for dilated cardiomyopathy". Genetics in Medicine. 12 (5): 268–78. doi:10.1097/GIM.0b013e3181d6f7c0. PMC 3018746. PMID 20474083.
• Malhotra A, Edelman-Novemsky I, Xu Y, Plesken H, Ma J, Schlame M, Ren M (February 2009). "Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome". Proceedings of the National Academy of Sciences of the United States of America. 106 (7): 2337–41. doi:10.1073/pnas.0811224106. PMC 2650157. PMID 19164547.
• van Werkhoven MA, Thorburn DR, Gedeon AK, Pitt JJ (October 2006). "Monolysocardiolipin in cultured fibroblasts is a sensitive and specific marker for Barth Syndrome". Journal of Lipid Research. 47 (10): 2346–51. doi:10.1194/jlr.D600024-JLR200. PMID 16873891.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Acehan D, Xu Y, Stokes DL, Schlame M (January 2007). "Comparison of lymphoblast mitochondria from normal subjects and patients with Barth syndrome using electron microscopic tomography". Laboratory Investigation; A Journal of Technical Methods and Pathology. 87 (1): 40–8. doi:10.1038/labinvest.3700480. PMC 2215767. PMID 17043667.
• Barth PG, Wanders RJ, Vreken P, Janssen EA, Lam J, Baas F (June 1999). "X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 302060)". Journal of Inherited Metabolic Disease. 22 (4): 555–67. doi:10.1023/A:1005568609936. PMID 10407787.
• Claypool SM, Boontheung P, McCaffery JM, Loo JA, Koehler CM (December 2008). "The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome". Molecular Biology of the Cell. 19 (12): 5143–55. doi:10.1091/mbc.E08-09-0896. PMC 2592642. PMID 18799610.
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (January 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
• McKenzie M, Lazarou M, Thorburn DR, Ryan MT (August 2006). "Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients". Journal of Molecular Biology. 361 (3): 462–9. CiteSeerX 10.1.1.314.3366. doi:10.1016/j.jmb.2006.06.057. PMID 16857210.
• Lu B, Kelher MR, Lee DP, Lewin TM, Coleman RA, Choy PC, Hatch GM (October 2004). "Complex expression pattern of the Barth syndrome gene product tafazzin in human cell lines and murine tissues". Biochemistry and Cell Biology. 82 (5): 569–76. doi:10.1139/o04-055. PMID 15499385.
• Ma L, Vaz FM, Gu Z, Wanders RJ, Greenberg ML (October 2004). "The human TAZ gene complements mitochondrial dysfunction in the yeast taz1Delta mutant. Implications for Barth syndrome". The Journal of Biological Chemistry. 279 (43): 44394–9. doi:10.1074/jbc.M405479200. PMID 15304507.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Houtkooper RH, Turkenburg M, Poll-The BT, Karall D, Pérez-Cerdá C, Morrone A, Malvagia S, Wanders RJ, Kulik W, Vaz FM (October 2009). "The enigmatic role of tafazzin in cardiolipin metabolism". Biochimica et Biophysica Acta. 1788 (10): 2003–14. doi:10.1016/j.bbamem.2009.07.009. PMID 19619503.
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (October 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
• Saunders MA, Slatkin M, Garner C, Hammer MF, Nachman MW (November 2005). "The extent of linkage disequilibrium caused by selection on G6PD in humans". Genetics. 171 (3): 1219–29. doi:10.1534/genetics.105.048140. PMC 1456824. PMID 16020776.
• Vaz FM, Houtkooper RH, Valianpour F, Barth PG, Wanders RJ (October 2003). "Only one splice variant of the human TAZ gene encodes a functional protein with a role in cardiolipin metabolism". The Journal of Biological Chemistry. 278 (44): 43089–94. doi:10.1074/jbc.M305956200. PMID 12930833.{{cite journal}}: CS1 maint: unflagged free DOI (link)

External links

• GeneReviews/NCBI/NIH/UW entry on Dilated Cardiomyopathy Overview
• TAZ+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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