Comparison of the molecular properties of retinitis pigmentosa P23H and N15S amino acid replacements in rhodopsin

MITCHELL, James, Fernanda BALEM, Kalyan TIRUPULA, David MAN, Harpreet Kaur DHIMAN, Naveena YANAMALA, Julian OLLESCH, Joan PLANAS IGLESIAS, Barbara J. JENNINGS, Klaus GERWERT, Alessandro IANNACCONE and Judith KLEIN-SEETHARAMAN. Comparison of the molecular properties of retinitis pigmentosa P23H and N15S amino acid replacements in rhodopsin. Plos one. San Francisco: Public Library of Science, 2019, vol. 14, No 5, p. 1-14. ISSN 1932-6203. Available from: https://dx.doi.org/10.1371/journal.pone.0214639.

Basic information

• Original name: Comparison of the molecular properties of retinitis pigmentosa P23H and N15S amino acid replacements in rhodopsin
• Authors: MITCHELL, James, Fernanda BALEM, Kalyan TIRUPULA, David MAN, Harpreet Kaur DHIMAN, Naveena YANAMALA, Julian OLLESCH, Joan PLANAS IGLESIAS (724 Spain, belonging to the institution), Barbara J. JENNINGS, Klaus GERWERT, Alessandro IANNACCONE and Judith KLEIN-SEETHARAMAN (guarantor).
• Edition: Plos one, San Francisco, Public Library of Science, 2019, 1932-6203.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10606 Microbiology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 2.740
• RIV identification code: RIV/00216224:14310/19:00113531
• Organization unit: Faculty of Science
• Doi: http://dx.doi.org/10.1371/journal.pone.0214639
• UT WoS: 000468176600003
• Keywords in English: POINT MUTATION; VITAMIN-A; MUTANTS; GENE; EXPRESSION; SUPPLEMENTATION; GLYCOSYLATION; IMPROVEMENT; STABILITY; BINDING
• Tags: rivok
• Tags: International impact, Reviewed

Abstract

Mutations in the RHO gene encoding for the visual pigment protein, rhodopsin, are among the most common cause of autosomal dominant retinitis pigmentosa (ADRP). Previous studies of ADRP mutations in different domains of rhodopsin have indicated that changes that lead to more instability in rhodopsin structure are responsible for more severe disease in patients. Here, we further test this hypothesis by comparing side-by-side and therefore quantitatively two RHO mutations, N15S and P23H, both located in the N-terminal intradiscal domain. The in vitro biochemical properties of these two rhodopsin proteins, expressed in stably transfected tetracycline-inducible HEK293S cells, their UV-visible absorption, their Fourier transform infrared, circular dichroism and Metarhodopsin II fluorescence spectroscopy properties were characterized. As compared to the severely impaired P23H molecular function, N15S is only slightly defective in structure and stability. We propose that the molecular basis for these structural differences lies in the greater distance of the N15 residue as compared to P23 with respect to the predicted rhodopsin folding core. As described previously for WT rhodopsin, addition of the cytoplasmic allosteric modulator chlorin e6 stabilizes especially the P23H protein, suggesting that chlorin e6 may be generally beneficial in the rescue of those ADRP rhodopsin proteins whose stability is affected by amino acid replacement.