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J. Biol. Chem., Vol. 276, Issue 25, 22388-22396, June 22, 2001
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From the Department of Biochemistry and Molecular Biology and
§ Department of Ophthalmology, University of British
Columbia, Vancouver, British Columbia V6T 1Z3, Canada
Peripherin-2 and Rom-1 are homologous
tetraspanning membrane proteins that assemble into noncovalent
tetramers and higher order disulfide-linked oligomers implicated in
photoreceptor disc morphogenesis. Individuals who coinherit a L185P
peripherin-2 mutation and a null or G113E
rom-1 mutation are afflicted with retinitis
pigmentosa, whereas individuals who inherit only one defective gene are
normal. We examined the expression, subunit assembly, and
disulfide-mediated oligomerization of L185P and L185A peripherin-2 and
L188P Rom-1 by velocity sedimentation, co-immunoprecipitation, and
cross-linking. These mutants formed noncovalent dimers under
disulfide-reducing conditions but failed to assemble into core
tetramers. Under nonreducing conditions, L185P dimers formed
disulfide-linked tetramers but not higher order oligomers. L185P
coassembled with wild-type peripherin-2 and Rom-1 to form tetramers and
higher order disulfide-linked oligomers characteristic of the wild-type
proteins. The G113E Rom-1 mutant expressed 20-fold lower than wild-type
Rom-1, indicating that it behaves mechanistically as a null allele. We
conclude that Leu185 of peripherin-2
(Leu188 of Rom-1) is critical for tetramer but not dimer
formation and that the core tetramer has 2-fold symmetry.
Peripherin-2-containing tetramers are required for higher order
disulfide-linked oligomer formation. The level of these oligomers is
critical for stable photoreceptor disc formation and the digenic
retinitis pigmentosa disease phenotype.
Molecular Characterization of Peripherin-2 and Rom-1 Mutants
Responsible for Digenic Retinitis Pigmentosa*
,
*
This work was supported by grants from the National Eye
Institute (EY 2422) and Foundation Fighting Blindness, Canada.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a predoctoral fellowship from the Foundation Fighting
Blindness, Canada.
¶
Holder of a Canada Research Chair in Vision and Macular
Degeneration. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, 2146 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia V6T 1Z3,
Canada. Tel.: 604-822-6173; Fax: 604-822-5227; E-mail:
molday@interchange.ubc.ca.
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