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In this work, we show that MeCP2 possesses properties akin to those of supercharged proteins. By utilizing its unstructured portions, MeCP2 can successfully transduce across cell membranes and localize to heterochromatic foci in the nuclei, displaying uptake levels a third lower than a MeCP2 construct fused to the cell\u2010penetrating peptide TAT. MeCP2 uptake can further be enhanced by the addition of compounds that promote endosomal escape following cellular trafficking by means of macropinocytosis. Using a combination of in silico prediction algorithms and live\u2010cell imaging experiments, we mapped the sequence in MeCP2 responsible for its cellular incorporation, which bears a striking resemblance to TAT itself. Transduced MeCP2 was shown to interact with HDAC3. These findings provide valuable insight into the properties of MeCP2 and may be beneficial for devising future protein\u2010based treatment strategies.<\/jats:p>","DOI":"10.1002\/pro.5170","type":"journal-article","created":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T11:40:50Z","timestamp":1726314050000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>MeCP2<\/scp> is a naturally supercharged protein with cell membrane transduction capabilities"],"prefix":"10.1002","volume":"33","author":[{"given":"Alexander V.","family":"Beribisky","sequence":"first","affiliation":[{"name":"Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna  Vienna 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