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Insertions or deletions of nucleotides not divisible by three shift the reading frames, resulting in significantly different protein sequences. These events are disruptive but can also create variability important for evolution. Previous studies suggested that the genetic code and gene sequences evolve to minimize frameshift effects, maintaining similar physicochemical properties to their reference proteins. Here, we focused on tandem repeat sequences, known as frameshift hotspots. Using cutting\u2010edge bioinformatics tools, we compared reference and frameshifted protein sequences within tandem repeats across 50 prokaryotic and eukaryotic proteomes. We showed that, in contrast to the general tendency, frameshifts within these regions, especially with short repeats, lead to a significant increase in hydrophobicity and arginine content. Additionally, the frameshifts, particularly in short tandem repeats, rearrange transmembrane regions, potentially converting soluble proteins into membrane proteins and vice versa. Given their occurrence in rapidly evolving, essential proteins, such changes may promote rapid adaptability. Our large\u2010scale\n                    <jats:sc>alphafold<\/jats:sc>\n                    modeling suggested that frameshift events can generate novel structures and functions, enabling the synthesis of multiple protein variants within the same coding region. Overall, frameshifts cause more drastic changes in tandem repeat sequences compared to non\u2010repetitive sequences and therefore can be a primary cause of altered functions, cellular localization, and the development of various pathologies.\n                  <\/jats:p>","DOI":"10.1111\/febs.70273","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T07:43:27Z","timestamp":1758699807000},"page":"842-858","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protein tandem repeats that produce frameshifts can generate new structural states and functions"],"prefix":"10.1111","volume":"293","author":[{"given":"Zarifa","family":"Osmanli","sequence":"first","affiliation":[{"name":"CRBM Universit\u00e9 de Montpellier, CNRS  France"},{"name":"Institute of Biophysics Ministry of Science and Education of Azerbaijan Republic  Baku Azerbaijan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gudrun","family":"Aldrian","sequence":"additional","affiliation":[{"name":"CRBM Universit\u00e9 de Montpellier, CNRS  France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Leclercq","sequence":"additional","affiliation":[{"name":"CRBM Universit\u00e9 de Montpellier, CNRS  France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theo","family":"Falgarone","sequence":"additional","affiliation":[{"name":"CRBM Universit\u00e9 de Montpellier, CNRS  France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santiago M.","family":"G\u00f3mez Bergna","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology and Molecular Biology (IBBM, UNLP\u2010CONICET), Faculty of Exact Sciences National University of La Plata  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis N.","family":"Prada Gori","sequence":"additional","affiliation":[{"name":"Laboratory of Bioactive Compound Research and Development (LIDeB), Faculty of Exact Sciences National University of La Plata  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew V.","family":"Oleinikov","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Charles E. 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