Crystal structure of the globular domain of C1QTNF5: Implications for late-onset retinal macular degeneration.

Publication Type:

Journal Article


J Struct Biol, Volume 180, Issue 3, p.439-46 (2012)


Amino Acid Sequence, Binding Sites, Cloning, Molecular, Collagen, Crystallography, X-Ray, Escherichia coli, Humans, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Macular Degeneration, Models, Molecular, Molecular Sequence Data, Mutation, Pigment Epithelium of Eye, Protein Binding, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Recombinant Proteins, Static Electricity


<p>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.</p>