Autosomal dominant late-onset retinal macular degeneration (L-ORMD) is caused by a single S163R mutation in the C1q and tumor necrosis factor-related protein 5 (C1QTNF5) gene. The C1QTNF5 gene encodes a secreted and membrane-associated protein involved in adhesion of retinal pigmented epithelial cells (RPE) to Bruch's membrane. The crystal structure of the trimeric globular domain of human C1QTNF5 at 1.34å resolution reveals unique features of this novel C1q family member. It lacks a Ca2+-binding site, displays a remarkable non-uniform distribution of surface electrostatic potentials and possesses a unique sequence (F181F182G183G184W185P186) that forms a hydrophobic plateau surrounded by Lys and Arg residues with a solvent cavity underneath. S163 forms a hydrogen bond with F182 in a hydrophobic area extending to the hydrophobic plateau. The pathogenic mutation S163R disrupts this hydrogen bonding and positively charges these hydrophobic areas. Thus, our analysis provides insights into the structural basis of the L-ORMD disease mechanism.
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We thank Drs. Philip D. Kiser and David L. Lodowski for help with data collection. We also thank Drs. Leslie T. Webster Jr., David L. Lodowski, and members of Palczewski’s laboratory (Case Western Reserve University) for valuable comments on the manuscript. This research was supported in part by Grants EY008061 and P30EY11373 from the National Institutes of Health . The work also is based upon research conducted at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines supported by Grants from the National Center for Research Resources ( 5P41RR015301-10 ) and the National Institute of General Medical Sciences ( 8P41GM103403-10 ) from the National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357.
- Age-related macular degeneration