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Originally published In Press as doi:10.1074/jbc.M107511200 on September 11, 2001

J. Biol. Chem., Vol. 276, Issue 46, 42700-42706, November 16, 2001
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Folding and Subunit Assembly of Photoreceptor Peripherin/rds Is Mediated by Determinants within the Extracellular/Intradiskal EC2 Domain
IMPLICATIONS FOR HETEROGENEOUS MOLECULAR PATHOLOGIES*

Andrew F. X. GoldbergDagger , Linda M. Fales, James B. Hurley§, and Nidhi Khattree

From the Eye Research Institute, Oakland University, Rochester, Michigan 48309 and § Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, Washington 98195

Peripherin/rds is an integral membrane protein required for the elaboration of rod and cone photoreceptor outer segments in the vertebrate retina; it causes a surprising variety of progressive retinal degenerations in humans and dysmorphic photoreceptors in murine models if defective or absent. (Peripherin/rds is also known as photoreceptor peripherin, peripherin/rds, rds/peripherin, rds, and peripherin-2.) Peripherin/rds appears to act as a structural element in outer segment architecture. However, neither its function at the molecular level nor its role in retinal disease processes are well understood. This report initiates a systematic investigation of protein domain structure and function by examining the molecular and cellular consequences of a series of 14 insertional mutations distributed throughout the polypeptide sequence. Protein expression, disulfide bonding, sedimentation velocity, and subcellular localization of the COS-1 cell-expressed mutant variants were examined to test the hypothesis that protein folding and tetrameric subunit assembly are mediated primarily by EC2, a conserved extracellular/intradiskal domain. Protein folding and tetrameric subunit assembly were not affected by insertion of either an uncharged dipeptide (GA) or a highly charged hendecapeptide (GDYKDDDDKAA) into any one of nine sites residing outside of EC2 as assayed by nonreducing Western blot analysis, sedimentation velocity, and subcellular localization. In contrast, insertions at five positions within the EC2 domain did cause either gross protein misfolding (two sites) or a reduction in protein sedimentation coefficient (two sites) or both (one site). These results indicate that although the vast majority of extramembranous polypeptide sequence makes no measurable contribution to protein folding and tetramerization, discrete regions within the EC2 domain do contain determinants for normal subunit assembly. These findings raise the possibility that multiple classes of structural perturbation are produced by inherited defects in peripherin/rds and contribute to the observed heterogeneity of retinal disease phenotypes.

* This work was supported by generous grants (Grants NIH R01 EY13246 to A. F. X. G . and NIH R01 EY06641 to J. B. H.) from the NEI National Institutes of Health.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.

Dagger To whom correspondence should be addressed: Eye Research Institute, Oakland University, Rochester, MI 48309. Tel.: 248-370-2393; Fax: 248-370-2006; E-mail: goldberg@oakland.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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