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. 2013 Jul 4;8(7):e67843.
doi: 10.1371/journal.pone.0067843. Print 2013.

Three-dimensional structure of human NLRP10/PYNOD pyrin domain reveals a homotypic interaction site distinct from its mouse homologue

Ming-Yuan Su  1 , Chiao-I Kuo, Chi-Fon Chang, Chung-I Chang
Affiliations

Three-dimensional structure of human NLRP10/PYNOD pyrin domain reveals a homotypic interaction site distinct from its mouse homologue

Ming-Yuan Su et al. PLoS One. .

Abstract

NLRPs (Nucleotide-binding domain, leucine-rich repeat and pyrin domain containing proteins) are a family of pattern-recognition receptors (PRRs) that sense intracellular microbial components and endogenous stress signals. NLRP10 (also known as PYNOD) is a unique NLRP member characterized by a lack of the putative ligand-binding leucine-rich repeat domain. Recently, human NLRP10 has been shown to inhibit the self-association of ASC into aggregates and ASC-mediated procaspase-1 processing. However, such activities are not found in mouse NLRP10. Here we report the solution structure and dynamics of human NLRP10 pyrin domain (PYD), whose helix H3 and loop H2-H3 adopt a conformation distinct from those of mouse NLRP10. Docking studies show that human and mouse NLRP10 PYDs may interact differently with ASC PYD. These results provide a possible structural explanation for the contrasting effect of NLRP10 on ASC aggregation in human cells versus mouse models. Finally, we also provide evidence that in human NLRP10 the PYD domain may not interact with the NOD domain to regulate its intrinsic nucleotide hydrolysis activity.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. NMR structure of huNLRP10 PYD.
(A) Ensemble of the 20 lowest-energy CYANA conformers, superimposed on the backbone atoms of the six helices, representing the structure of huNLRP10 PYD. (B) Ribbon representation of the lowest-energy structure in the same orientation ass in (A). The six helices, as well as the N-and C-termini, are labeled.
Figure 2
Figure 2. Sequence alignment of huNLRP10 PYD with other PYDs.
(A) Sequence alignment of huNLRP10 and muNLRP10s and ASCs. Experimentally determined -helices of huNLRP10 PYD are depicted by gray rectangles above the sequences. Helical residues of all other PYDs with known structures are underlined. The tetrapeptide insertion and replaced dipeptide sequences in the H2–H3 loop of huNLRP10 are shaded in violet. Acidic and basic residues determined previously in ASC PYD to be critical for self-association and interacting with other PYDs are colored in red and blue, respectively , ; the corresponding acidic and basic residues, located on the H1–H4 and H2–H3 surfaces of huNLRP10 PYD are shaded in red and cyan, respectively. Residues forming the hydrophobic core are shaded in yellow. Symbols below the aligned sequences are: “*” for identical residues; “:” for conserved residues; “.” for semi-conserved residues.
Figure 3
Figure 3. Backbone dynamics of huNLRP10.
NMR relaxation data of backbone amide (15N) measured as heteronuclear Overhauser values (15N{1H}- NOE) showing local motions on a fast time scale (ps to ns) of the residues in the H2–H3 loop and helix H3 regions.
Figure 4
Figure 4. Structures of huNLRP10 and muNLRP10 PYDs.
(A) Ribbon representation of huNLRP10 PYD with the H2–H3 loop highlighted in orange. (B) Ribbon representation of muNLRP10 PYD (PDB code 2DO9), in identical orientation as huNLRP10 PYD shown in (A), with the highlighted region corresponding to the H2–H3 loop of the human homologue. Residues in sticks are labeled and discussed in main text. (C) Stereo view showing the superimposed structures of huNLRP10 PYD (blue) and muNLRP10 PYD (cyan).
Figure 5
Figure 5. Docking analysis of huNLRP10 and muNLRP10 PYDs with ASC PYD.
Superposition of the top 10 docking models of the huNLRP10 PYD-ASC PYD complex (A) and of the muNLRP10 PYD-ASC PYD complex (B) predicted by ClusPro (http://nrc.bu.edu/cluster). Note that none of the top 10 models of the mouse complex involves the H1–H4 surface of muNLRP10 PYD. The docked huASC and muASC PYD models are shown in backbone traces with different colors. The huNLRP10 and muNLRP10 PYDs, defined as the receptors for docking, are rendered in marine- and cyan-colored ribbons, respectively; the conserved basic and acidic residues shown in blue and red sticks, respectively, were identified previously to be important in ASC PYD for self-association.
Figure 6
Figure 6. Surface electrostatic potential of the PYDs of huNLRP10, muNLRP10, and other PYDs.
All surface representations of the PYDs are shown in the same orientation as the ribbon model of huNLRP10 on the upper left, with the H2–H3 and the H1–H4 surfaces on the left side and the right side, respectively, of each model. Positive surface charge is colored in blue; negative surface charge is colored red; and neutral surface is in white. The exposed basic and acidic residues on the two surfaces are shown as sticks in the ribbon representation of huNLRP10.
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This work was supported in part by the National Science Council of Taiwan (http://web1.nsc.gov.tw) under grant nos. NSC99-2320-B-001-MY2 and NSC 101-2811-M-001-164. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.