Abstract
Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations in the peripherin-2 homolog Rom-1 cause digenic RP in combination with certain heterozygous mutations in peripherin-2. The mechanisms underlying the differential role of peripherin-2 and Rom-1 in RP pathophysiology remained elusive so far. Here, focusing on two adRP-linked peripherin-2 mutants, P210L and C214S, we analyzed the binding characteristics, protein assembly, and rod OS targeting of wild type (per(WT)), mutant peripherin-2 (per(MT)), or Rom-1 complexes, which can be formed in patients heterozygous for peripherin-2 mutations. Both mutants are misfolded and lead to decreased binding to per(WT) and Rom-1. Furthermore, both mutants are preferentially forming non-covalent per(MT)-per(MT), per(WT)-per(MT), and Rom-1-per(MT) dimers. However, only per(WT)-per(MT), but not per(MT)-per(MT) or Rom-1-per(MT) complexes could be targeted to murine rod OS. Our study provides first evidence that non-covalent per(WT)-per(MT) dimers can be targeted to rod OS. Finally, our study unravels unexpected opposing roles of per(WT) and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants and suggests a new treatment strategy for the affected individuals.
Item Type: | Journal article |
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Faculties: | Chemistry and Pharmacy > Department of Pharmacy |
Research Centers: | Center for Integrated Protein Science Munich (CIPSM) |
Subjects: | 500 Science > 540 Chemistry |
URN: | urn:nbn:de:bvb:19-epub-54459-8 |
ISSN: | 2045-2322 |
Language: | English |
Item ID: | 54459 |
Date Deposited: | 14. Jun 2018, 09:56 |
Last Modified: | 04. Nov 2020, 13:34 |