Novel transglutaminase-like peptidase and C2 domains elucidate the structure, biogenesis and evolution of the ciliary compartment - PubMed (original) (raw)

. 2012 Oct 15;11(20):3861-75.

doi: 10.4161/cc.22068. Epub 2012 Sep 14.

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Novel transglutaminase-like peptidase and C2 domains elucidate the structure, biogenesis and evolution of the ciliary compartment

Dapeng Zhang et al. Cell Cycle. 2012.

Abstract

In addition to their role in motility, eukaryotic cilia serve as a distinct compartment for signal transduction and regulatory sequestration of biomolecules. Recent genetic and biochemical studies have revealed an extraordinary diversity of protein complexes involved in the biogenesis of cilia during each cell cycle. Mutations in components of these complexes are at the heart of human ciliopathies such as Nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), Bardet-Biedl syndrome (BBS) and Joubert syndrome (JBTS). Despite intense studies, proteins in some of these complexes, such as the NPHP1-4-8 and the MKS, remain poorly understood. Using a combination of computational analyses we studied these complexes to identify novel domains in them which might throw new light on their functions and evolutionary origins. First, we identified both catalytically active and inactive versions of transglutaminase-like (TGL) peptidase domains in key ciliary/centrosomal proteins CC2D2A/MKS6, CC2D2B, CEP76 and CCDC135. These ciliary TGL domains appear to have originated from prokaryotic TGL domains that act as peptidases, either in a prokaryotic protein degradation system with the MoxR AAA+ ATPase, the precursor of eukaryotic dyneins and midasins, or in a peptide-ligase system with an ATP-grasp enzyme comparable to tubulin-modifying TTL proteins. We suggest that active ciliary TGL proteins are part of a cilia-specific peptidase system that might remove tubulin modifications or cleave cilia- localized proteins, while the inactive versions are likely to bind peptides and mediate key interactions during ciliogenesis. Second, we observe a vast radiation of C2 domains, which are key membrane-localization modules, in multiple ciliary proteins, including those from the NPHP1-4-8 and the MKS complexes, such as CC2D2A/MKS6, RPGRIP1, RPGRIP1L, NPHP1, NPHP4, C2CD3, AHI1/Jouberin and CEP76, most of which can be traced back to the last common eukaryotic ancestor. Identification of these TGL and C2 domains aid in the proper reconstruction of the Y-shaped linkers, which are key structures in the transitional zone of cilia, by allowing precise prediction of the multiple membrane-contacting and protein-protein interaction sites in these structures. These findings help decipher key events in the evolutionary separation of the ciliary and nuclear compartments in course of the emergence of the eukaryotic cell.

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Figures

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Figure 1A and B. (A) Multiple sequence alignment of the core region of TGL domains from bacterial and eukaryotic ciliary proteins. The catalytic triad residues (C/S, H, E/D) are labeled with number sign (#) and highlighted in red background. Secondary structures are shown with α-helices in pink and β-strands in light blue. Domain architectures of each ciliary TGL domains are shown below the alignment. Proteins are denoted by their gene name, species abbreviations and GI (GenBank Index) numbers separated by underscores. For species abbreviations, refer to the Materials and Methods section. (B) Divergent evolution of ciliary TGL domains prior to LECA. Capital L in the circle indicates the presence of the domain in the LECA. The tree was reconstructed using an approximately maximum-likelihood method implemented in the FastTree 2.1 program under default parameters. Bootstrap values are shown at each node.

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Figure 1C. A predicted model of eukaryotic TGLs involved in ciliary tubulin modifications and the evolutionary links to the bacterial protein degradation and peptide tagging systems. Canonical operons representing both bacterial protein degradation and peptide tagging systems are shown on the top. Light gray arrowed lines indicate gene transfer events and dark arrowed lines (and dashed ones) indicate known (and predicted) biochemical actions.

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Figure 2. Multiple sequence alignment and domain architectures of novel C2 domains of ciliary proteins CC2D2A (A), CEP76 (B) and RPGRIP1 (C). For species abbreviations, refer to the Materials and Methods section.

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Figure 3. Multiple sequence alignment and domain architectures of novel C2 domains of ciliary proteins, such as NPHP1 (A), NPHP4 (B), C2CD3 (C) and AHI1 (D). For species abbreviations, refer to the Materials and Methods section.

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Figure 4. Evolutionary relationship of the different C2 domain families and the comparison of their phyletic patterns, functions and features of domain architecture. The tree was reconstructed using an approximately maximum-likelihood method implemented in the FastTree 2.1 program under default parameters. Nodes supported with bootstrap values greater than 75% are shown.

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