{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T08:13:09Z","timestamp":1794557589143,"version":"4.9.1"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"24","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"HHS | NIH | National Eye Institute","doi-asserted-by":"publisher","award":["R01EY009339; R01EY030873"],"award-info":[{"award-number":["R01EY009339; R01EY030873"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"HHS | NIH | National Eye Institute","doi-asserted-by":"publisher","award":["P30EY034070"],"award-info":[{"award-number":["P30EY034070"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,16]]},"abstract":"<jats:p>Tetrameric rod phosphodiesterase-6 (PDE6), comprised of an \u03b1\/\u03b2 heterodimeric catalytic core and two inhibitory \u03b3 subunits, critically regulates cyclic GMP (cGMP) levels in rod photoreceptors. While the rod-PDE6 catalytic core is a heterodimer, the cone isoform is an \u03b1\u2032\/\u03b1\u2032 homodimer. This structural difference suggests a unique role for each rod subunit. Due to the lack of heterologous expression systems, we generated four transgenic mouse models to examine the functional contributions of the N-terminal pony-tail (Pt)-motifs and of the catalytic domains of the individual catalytic subunits of rod PDE6 in vivo. We generated two N-terminal deletions (PDE6\u03b1\u03942-48AA and PDE6\u03b2\u03942-46AA); and two active-site mutations (PDE6\u03b1H599A and PDE6\u03b2H597A) designed to selectively abolish catalytic activity. Native mass spectrometric analysis of heterozygous mice revealed that only wild-type enzyme was produced. While homozygous mutations in all lines caused complete photoreceptor degeneration, analysis of heterozygous lines revealed a disproportionately greater impact of \u03b2-subunit mutations on protein stability, enzymatic activity, and visual function. These findings establish that both active subunits are essential for rod integrity, but a significant functional asymmetry exists within the PDE6\u03b1\u03b2 heterodimer. Our results demonstrate that the PDE6\u03b2 subunit plays a more dominant role in maintaining the structural and functional pool of PDE6 enzyme.<\/jats:p>","DOI":"10.1073\/pnas.2604088123","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T19:08:11Z","timestamp":1780945691000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Functional asymmetry and essential structural roles of PDE6\u03b1 and PDE6\u03b2 subunits in rod\u2013photoreceptor integrity"],"prefix":"10.1073","volume":"123","author":[{"given":"Roman","family":"Smidak","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04gyf1771","id-type":"ROR","asserted-by":"publisher"}],"name":"Brunson Center for Translational Vision Research, Department of Ophthalmology and Visual Sciences, Gavin Herbert Eye Institute, University of 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