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RPGR function requires glutamylation by tubulin tyrosine ligase-like 5 (TTLL5) whose mutation is also linked to severe forms of retinal degeneration. How TTLL5 targets RPGR and how mutations in either protein cause disease are unknown. Here we report the 2.8-\u00c5 X-ray crystal structure of the coactivator interacting domain (CID) of human TTLL5 in complex with the RPGR C terminus, both required for glutamylation. The RPGR C terminus forms a helix that intercalates through aromatic interactions into the CID helical bundle of novel fold. Interfacial residues are mutated in retinitis pigmentosa, as well as macular degeneration of unknown etiology. Key mutations at this interface abolish RPGR\u2013TTLL5 interaction in vitro and RPGR glutamylation in mouse photoreceptors. Our work reveals mechanisms of non-tubulin substrate recognition by TTLL glutamylases, increasingly recognized as broad regulators of the proteome, and sheds light on mechanisms of disease associated with TTLL5 and RPGR mutations.<\/jats:p>","DOI":"10.1083\/jcb.202508020","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T07:21:07Z","timestamp":1772522467000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Insights into retinal disease and non-tubulin glutamylation from a RPGR\u2013TTLL5 complex structure"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1377-1707","authenticated-orcid":true,"given":"James H.","family":"Park","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Biophysics Unit, National Institute of Neurological Disorders and Stroke 1 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1667-4344","authenticated-orcid":true,"given":"Richard J.Y.","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Biophysics Unit, National Institute of Neurological Disorders and Stroke 1 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4704-2801","authenticated-orcid":true,"given":"Xun","family":"Sun","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}],"name":"Retinal Cell Biology & Degeneration Section, National Eye Institute 2 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3202-851X","authenticated-orcid":true,"given":"Kishore K.","family":"Mahalingan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Biophysics Unit, National Institute of Neurological Disorders and Stroke 1 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6391-7529","authenticated-orcid":true,"given":"Suja","family":"Hiriyanna","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}],"name":"Retinal Cell Biology & Degeneration Section, National Eye Institute 2 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9537-2573","authenticated-orcid":true,"given":"Tiansen","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}],"name":"Retinal Cell Biology & Degeneration Section, National Eye Institute 2 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2621-7307","authenticated-orcid":true,"given":"Antonina","family":"Roll-Mecak","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Biophysics Unit, National Institute of Neurological Disorders and Stroke 1 , Bethesda, MD,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}],"name":"Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute 3 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"2026040612262703700_bib1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"2026040612262703700_bib2","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1107\/S0907444912001308","article-title":"Towards automated crystallographic structure refinement with phenix.refine","volume":"68","author":"Afonine","year":"2012","journal-title":"Acta Crystallogr. 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