Biophysical and Structural Characterization of the Centriolar Protein Cep104 Interaction Network

Rezabkova, Lenka; Kraatz, S.H.W.; Akhmanova, Anna; Steinmetz, Michel O.; Kammerer, Richard A.

doi:10.1074/jbc.m116.739771

Cited by 35 publications

(48 citation statements)

References 37 publications

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“…Our results show that human Cep104 contains a TOG domain that is structurally similar to other tubulin-binding TOG domains and engages tubulin through residues that are conserved between these. While our manuscript was in preparation, the TOG domain of chicken Cep104 was reported by another group (Rezabkova et al., 2016). Their TOG structure and analysis of the tubulin-interacting interface are in good agreement with our results.…”

Section: Discussionsupporting

confidence: 58%

“…Recently CP110 has been shown to interact with a section of Cep104 that contains its putative ZNF array, and the interacting region in CP110 has subsequently been mapped to CP110 907−936 (Jiang et al., 2012, Rezabkova et al., 2016). Given that both CP110 and Nek1 bind to the Cep104 ZNF array, we asked whether they share the same binding site or could engage their target sites on the Cep104 ZNF array simultaneously.…”

Section: Resultsmentioning

confidence: 99%

“…It is currently thought that the XMAP215 family of MAPs requires at least two TOG domains to function (Ayaz et al., 2014, Widlund et al., 2011), but our analysis revealed only a single TOG domain in Cep104. However, Cep104 contains two coiled-coil regions (Figure 1A), one of which forms dimers (Rezabkova et al., 2016). Thus, Cep104 might have two TOG domains that could function in vivo.…”

Section: Discussionmentioning

confidence: 99%

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The Ciliopathy-Associated Cep104 Protein Interacts with Tubulin and Nek1 Kinase

et al. 2017

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SummaryCilia are thin cell projections with essential roles in cell motility, fluid movement, sensing, and signaling. They are templated from centrioles that dock against the plasma membrane and subsequently extend their peripheral microtubule array. The molecular mechanisms underpinning cilia assembly are incompletely understood. Cep104 is a key factor involved in cilia formation and length regulation that rides on the ends of elongating and shrinking cilia. It is mutated in Joubert syndrome, a genetically heterogeneous ciliopathy. Here we provide structural and biochemical data that Cep104 contains a tubulin-binding TOG (tumor overexpressed gene) domain and a novel C2HC zinc finger array. Furthermore, we identify the kinase Nek1, another ciliopathy-associated protein, as a potential binding partner of this array. Finally, we show that Nek1 competes for binding to Cep104 with the distal centriole-capping protein CP110. Our data suggest a model for Cep104 activity during ciliogenesis and provide a novel link between Cep104 and Nek1.

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Section: Discussionsupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Ciliopathy-Associated Cep104 Protein Interacts with Tubulin and Nek1 Kinase

et al. 2017

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“…However, we know little about how flagellum tip structures form during flagellum assembly, how they change postaxoneme assembly, or their molecular composition. There is only a single well-characterized protein (FAP256/CEP104) known to be related to structures at the distal end of the axoneme (10,11).…”

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confidence: 99%

Protein diversity in discrete structures at the distal tip of the trypanosome flagellum

Varga

Moreira-Leite

Portman

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The distal end of the eukaryotic flagellum/cilium is important for axonemal growth and signaling and has distinct biomechanical properties. Specific flagellum tip structures exist, yet their composition, dynamics, and functions are largely unknown. We used biochemical approaches to identify seven constituents of the flagella connector at the tip of an assembling trypanosome flagellum and three constituents of the axonemal capping structure at the tips of both assembling and mature flagella. Both tip structures contain evolutionarily conserved as well as kinetoplastid-specific proteins, and component assembly into the structures occurs very early during flagellum extension. Localization and functional studies reveal that the flagella connector membrane junction is attached to the tips of extending microtubules of the assembling flagellum by a kinesin-15 family member. On the opposite side, a kinetoplastid-specific kinesin facilitates attachment of the junction to the microtubules in the mature flagellum. Functional studies also suggest roles of several other components and the definition of subdomains in the tip structures.

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“…They also found that loss of CEP104 caused ciliogenesis defect in both Chlamydomonas and human RPE‐1 cells (Satish Tammana et al, ). The biophysical and structural work showed that CEP104 was a multidomain protein and interacted with several cilia and microtubule‐related proteins, including CP110 , CEP97 , end‐binding protein, and tubulin (Al‐Jassar et al, ; Louka et al, ; Rezabkova, Kraatz, Akhmanova, Steinmetz, & Kammerer, ). The c.414delC mutation led to the loss of two CC domains, TOG domain, and the tandem ZNF repeats, which caused the missing of the major functional part of CEP104 (Al‐Jassar et al, ; Rezabkova et al, ) (Figure a,b).…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing reveals novel CEP104 mutations in a Chinese patient with Joubert syndrome

Luo

Cao

et al. 2019

Molec Gen & Gen Med

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BackgroundJoubert syndrome (JS, OMIM: 213300) is a recessive developmental disorder characterized by cerebellar vermis hypoplasia and a distinctive mid‐hindbrain malformation called the “molar tooth sign” on axial magnetic resonance imaging. To date, more than 35 ciliary genes have been identified as the causative genes of JS.MethodsWhole exome sequencing was performed to detect the causative gene mutations in a Chinese patient with JS followed by Sanger sequencing. RT‐PCR and Sanger sequencing were used to confirm the abnormal transcript of centrosomal protein 104 (CEP104, OMIM: 616690).ResultsWe identified two novel heterozygous mutations of CEP104 in the proband, which were c.2364+1G>A and c.414delC (p.Asn138Lysfs*11) (GenBank: NM_014704.3) and consistent with the autosomal recessive inheritance mode.ConclusionOur study reported the fourth case of JS patients with CEP104 mutations, which expands the mutation spectrum of CEP104 and elucidates the clinical heterogeneity of JS.

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Biophysical and Structural Characterization of the Centriolar Protein Cep104 Interaction Network

Cited by 35 publications

References 37 publications

The Ciliopathy-Associated Cep104 Protein Interacts with Tubulin and Nek1 Kinase

The Ciliopathy-Associated Cep104 Protein Interacts with Tubulin and Nek1 Kinase

Protein diversity in discrete structures at the distal tip of the trypanosome flagellum

Whole exome sequencing reveals novel CEP104 mutations in a Chinese patient with Joubert syndrome

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