Deficient geranylgeranylation of Ram/Rab27 in choroideremia
Open accessAbstract
Choroideremia, an X-linked form of retinal degeneration, results from defects in the Rab escort protein-1 (REP-1) gene. REP-1 and REP-2 assist in the attachment of geranylgeranyl groups to Rab GTPases, a modification essential for their action as molecular switches regulating intracellular vesicular transport. If Rabs that depend preferentially on REP-1 for prenylation exist, they will accumulate unprenylated in choroideremia cells. Using recombinant Rab geranylgeranyl transferase and REPs to label unprenylated cytosolic proteins, we identified one unprenylated protein in choroideremia lymphoblasts that was prenylated in vitro more efficiently by REP-1 than by REP-2. This protein was purified and identified as Ram (renamed Rab27), a previously cloned Rab of unknown function. Immunohistochemistry of rat retina showed that Ram/Rab27 is expressed in the pigment epithelium and choriocapillaris, the two retinal cell layers that degenerate earliest in choroideremia. These results raise the possibility that the retinal degeneration in choroideremia results from the deficient geranylgeranylation of Ram/Rab27 or a closely related protein.
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Mutant CHM results in underprenylated RAB27A, which is the RAB that links myosin-7a to melanosomes.
“Interestingly, mutant CHM results in underprenylated RAB27A (Seabra et al., 1995), which is the RAB that links myosin-7a to melanosomes (Futter et al., 2004; Gibbs et al., 2004).”
From Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis (2015) · cites this paper as Seabra et al., 1995
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- Authors
- Seabra, M. C., Ho, Y. K., & Anant, J. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Seabra, Miguel C.
- ORCID
- Seabra, Miguel C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-10
- Volume
- 270
- Issue
- 41
- Pages
- 24420-24427
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2057777449
- Cited by
- 223
- References
- 32
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 8 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 9 · 2013: 6 · 2012: 6
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- European Molecular Biology Laboratory
- National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- choroideremia, Rab GTPases, geranylgeranylation, prenylation, X-linked retinal degeneration, retinal pigment epithelium, choriocapillaris, vesicle trafficking
- MeSH terms
- rab27 GTP-Binding Proteins, Adult, Animals, Base Sequence, Carrier Proteins, Cell Line, Chromatography, Gel, Chromatography, Ion Exchange, Cloning, Molecular, Escherichia coli, Female, Humans, Kinetics, Lymphocytes, Male, Molecular Sequence Data, Recombinant Proteins, Transferases, X Chromosome, Choroideremia, Protein Prenylation, DNA Primers, GTP-Binding Proteins, Alkyl and Aryl Transferases, rab GTP-Binding Proteins, Adaptor Proteins, Signal Transducing, Rats
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