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Mutations in TANGO2 result in mitochondrial dysfunction, abnormal lipid homeostasis with cardiolipin deficiency, and impaired Golgi\u2010ER trafficking in TANGO2 patient\u2010derived cells. Despite the wide recognition of the clinical manifestations of TDD and numerous molecular studies, the precise function of TANGO2 and the pathophysiology of TDD remain poorly understood. A computationally derived three\u2010dimensional structure model suggested that TANGO2 adopts an \u03b1\u03b2\u03b2\u03b1\u2010fold, similar to the N\u2010terminal nucleophile aminohydrolase (Ntn) superfamily of proteins, but the experimentally verified structure has not been available thus far. Here, we present the first crystal structure of the recombinant human TANGO2, determined at 1.70\u2009\u00c5 resolution. The X\u2010ray structure data confirmed its predicted tertiary fold with similarity to the Ntn\u2010hydrolase family of proteins, and the comparative analysis of the active site architecture, including residues involved in catalysis and putative ligand binding site, suggests a potential hydrolase function. Additional examination of the common mutation sites found in TDD patients provides insight regarding their potential effect on protein structure integrity.<\/jats:p>","DOI":"10.1002\/prot.70023","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T06:53:56Z","timestamp":1753772036000},"page":"515-528","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Crystal Structure of Human Transport and Golgi Organization 2 Homolog (\n                    <scp>TANGO2<\/scp>\n                    ) Protein Reveals an \u03b1\u03b2\u03b2\u03b1\u2010Fold Arrangement"],"prefix":"10.1002","volume":"94","author":[{"given":"Anne","family":"Cooper","sequence":"first","affiliation":[{"name":"Protein Structure and X\u2010Ray Crystallography Laboratory, Del Shankel Structural Biology Center University of Kansas  Lawrence Kansas 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