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. 2012 Dec;180(3):439-46.
doi: 10.1016/j.jsb.2012.07.011. Epub 2012 Aug 7.

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

Xiongying Tu  1 , Krzysztof Palczewski
Affiliations

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

Xiongying Tu et al. J Struct Biol. 2012 Dec.

Abstract

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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Figures

Fig. 1
Fig. 1
Domain organization of C1QTNF5 and sequence alignment of members of the C1q family proteins. A. The domain structure of C1QTNF5. B. A bouquet-like arrangement of the C1q family proteins. Figure adapted from (Francis et al., 2003) with permission from the authors and publisher. The three protomers are shown in magenta, green and cyan. The trimeric globular head is outlined by a black box. The top and base of the globular head are indicated by arrows. C. Sequence alignment of gC1q domains from C1q family proteins. Sequences are those of human C1QTNF5, human complement protein C1q (PDB ID: 1PK6), human collagen X NC1 (PDB ID: 1GR3), human collagen VIII NC1 (PDB ID: 1O91), and human adiponectin (PDB ID: 4DOU). Conserved residues are highlighted in white letters with background colors ranging from blue to black according to their conservation. The conserved hydrophobic motif (residues 143–153) and the F181F182G183G184W185P186 sequence are outlined in red. S163 is marked with an asterisk. Key aspartic acids coordinating with Ca2+ ions are highlighted in red. Secondary structure is assigned according to the structure of the trimeric head of human C1QTNF5.
Fig. 2
Fig. 2
Structure of the homotrimeric head of human C1QTNF5. A. Overall structure. B. Closeup view of the hydrophobic ‘zipper’ of protomer A and the hydrophobic core of the central interface. C. Close-up view of the solvent cavity at the central interface (protomer B is not shown). D. Close-up view of the hydrophobic plateau on the top of the trimeric head. Protomers A, B and C are colored gray, pink, and yellow, respectively. The vertical lines showed in the overall structure represent 3-fold axis at the central interface. Carbon atoms of the conserved hydrophobic residues that form the ‘zipper’ are shown in cyan for protomer A. The ‘zipper’ box and hydrophobic core are outlined with red and black ovals, respectively. Water molecules are represented by orange spheres. Hydrogen bond distances have unit of Å.
Fig. 3
Fig. 3
Comparison of electrostatic potentials on surfaces of selected structures of known C1q family proteins viewed from the top, side and bottom. Molecular surfaces are colored according to their electrostatic potentials with a color scale set from −7 kT/e (red) to 7 kT/e (blue), as calculated by the Adaptive Poisson-Boltzmann Solve (APBS) implemented in PyMOL software (Baker et al., 2001; Schrödinger). Positive potentials are shown in blue, negative potentials in red, and hydrophobicity in white. (a) The homotrimeric head of human C1QTNF5; (b) the heterotrimeric head of human complement protein C1q; (c) the homotrimeric head of human adiponectin.
Fig. 4
Fig. 4
Pathogenic S163R mutation. A. S163 forms a hydrogen bond with F182. The hydrogen bond of S163 positions and stabilizes the apical loop. S163 is enwrapped by hydrophobic residues A162, F179, F181, F182, and Y214. B. Arg163 disrupts this hydrogen bond, changing the electrostatic potentials in this area and causing separation of the involved residues. Electrostatic potentials of surfaces around S163 (C) and modeled R163 (D) of human C1QTNF5. The molecular surfaces are colored according to electrostatic potential with color scale set from −7 kT/e (red) to 7 kT/e (blue), as calculated by APBS implemented in PyMOL. Positive potentials are shown in blue, negative potentials in red, and hydrophobicity is in white. Hydrogen bond distances have unit of Å.
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