Tafazzin is a protein that in humans is encoded by the TAFAZZIN 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 TAFAZZIN 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 TAFAZZIN 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. The TAZ gene was frequently confused with a protein called TAZ (transcriptional coactivator with PDZ-binding motif, a 50 kDa protein). which is a part of the Hippo pathway and entirely unrelated to the gene of interest. The Hippo pathway TAZ protein has an official gene symbol of WWTR1.
History Tafazzin was discovered in 1996 by Italian scientists Silvia Bione et al., after long and intensive work. Owing to the complex procedure required for the identification of tafazzin, the protein was named after Tafazzi, a comedic character who enthusiastically beats his groin with a plastic bottle, and whose masochistic traits resonated with the discoverers of the protein.
Structure The TAFAZZIN gene is located on the q arm of chromosome X at position 28 and it spans 10,208 base pairs. The TAFAZZIN 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 four different isoforms. It has a molecular weight around 35 kDa but may also appear in lower molecular weights due to species differences in isoform expression. Seven functional classes of TAFAZZIN mutations have been classified based on the pathogenic loss-of-function mechanisms of each mutation. The TAFAZZIN 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 TAFAZZIN 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.
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