Crescerin uses a TOG domain array to regulate microtubules in the primary cilium

Das, Alakananda; Dickinson, Daniel J.; Wood, Cameron C.; Goldstein, Bob; Slep, Kevin C.

doi:10.1091/mbc.e15-08-0603

Cited by 62 publications

(124 citation statements)

References 64 publications

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“…Using strep -FLAG epitope-tagged ARMC9 expressed in HEK293T cells, followed by tandem affinity purification (TAP) and subsequent mass spectrometry, we identified 116 candidate ARMC9 interactors, including the known JBTS-associated proteins CEP290, CEP104, CSPP1 ( Figure 1A, B; Supplemental table 1). Within the data set, ARMC9, CEP104, CCDC66, and TOGARAM1/Crescerin-1 were chosen for further characterization as they are microtubule-associated proteins previously implicated in cilium function (26,28,29). Coimmunoprecipitation (co-IP) confirmed the interaction between TOGARAM1 and ARMC9 ( Figure 1C).…”

Section: Identification Of a Novel Protein Module Implicated In Jbtsmentioning

confidence: 85%

“…TOGARAM1 has four conserved TOG domains that display similarity to the tubulin binding domains in ch-TOG and CLASP family proteins {Das:2015cv}. Arg368Trp and Leu375Pro lie within the highly conserved TOG2 domain ( Figure 2A) which has been found to promote microtubule polymerization in vitro (26). The TOG2 domain conforms to the canonical TOG domain architecture found in other TOG array containing proteins such as CLASP and Stu2 (Supplemental Figure 2A, D), therefore disruption of this domain is predicted to disturb microtubule binding (35).…”

Section: Jbts-associated Togaram1 Variants In the Tog2 Domain Disruptmentioning

confidence: 99%

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ARMC9 and TOGARAM1 define a Joubert syndrome-associated protein module that regulates axonemal post-translational modifications and cilium stability

Latour

Weghe

Rusterholz

et al. 2019

Preprint

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Joubert syndrome (JBTS) is a recessive neurodevelopmental ciliopathy, characterized by a pathognomonic hindbrain malformation. All known JBTS-genes encode proteins involved in the structure or function of primary cilia, ubiquitous antenna-like organelles essential for cellular signal transduction. Here, we use the recently identified JBTS-associated protein ARMC9 in tandem-affinity purification and yeast twohybrid screens to identify a novel ciliary module composed of ARMC9-TOGARAM1-CCDC66-CEP104-CSPP1. TOGARAM1-variants cause JBTS and disrupt its interaction with ARMC9. Using a combination of protein interaction analyses and characterization of patient-derived fibroblasts, CRISPR/Cas9-engineered zebrafish and hTERT-RPE1 cells, we demonstrate that dysfunction of ARMC9 or TOGARAM1 results in short cilia with decreased axonemal acetylation and glutamylation, but relatively intact transition zone function. Aberrant serum-induced ciliary resorption and cold-induced depolymerization in both ARMC9 and TOGARAM1 patient cells lines suggest a role for this new JBTS-associated protein complex in ciliary stability.part by the transition zone (TZ) that connects the axoneme to the membrane and acts as a partition.Approximately half of the known JBTS proteins, including RPGRIP1L (JBTS7) (14) and CC2D2A (JBTS9) (15), assemble into multi-protein complexes at the ciliary TZ where they are thought to organize the molecular gate that regulates ciliary protein entry and exit (16); and dysfunction of TZ organization is thought to play a key role in JBTS. Another subset of JBTS-associated proteins, including ARL13B (JBTS8) and INPP5E (JBTS1) (6), associate with the ciliary membrane beyond the TZ. These proteins are thought to play a role in regulation of signaling pathways such as Hh signaling via maintenance of ciliary lipid composition (17, 18). Different JBTS-associated proteins have been found to function at the basal body or distal segment/tip (4). CSPP1 (JBTS 21) (19) and CEP104 (JBTS25) (20) were mainly detected at the centrosomes and ciliary basal bodies, however their exact molecular function, and how defects in these proteins lead to JBTS, are less well understood. CEP104 localizes to the ciliary tip during ciliogenesis, where it is required for structural integrity in the motile cilia of Chlamydomonas and Tetrahymena (21, 22). Mutations in the gene encoding the ciliary tip kinesin KIF7 (JBTS12) cause JBTS, which were linked to defects in tubulin acetylation and Hedgehog signaling (23).Recently, we identified mutations in the gene encoding armadillo repeat motif containing 9 (ARMC9) in individuals with JBTS (JBTS30). ARMC9 localizes to centrioles (27) and the proximal portion of the cilium (28) in mammalian cilia. ARMC9 transcript levels are upregulated with induction of ciliogenesis and armc9 dysfunction in zebrafish yields typical ciliopathy phenotypes (27). As ARMC9 has not been identified as a component of the ciliary JS-associated protein modules mentioned above, we here use ARMC9 as a bait in protein interaction screen...

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Section: Identification Of a Novel Protein Module Implicated In Jbtsmentioning

confidence: 85%

Section: Jbts-associated Togaram1 Variants In the Tog2 Domain Disruptmentioning

confidence: 99%

ARMC9 and TOGARAM1 define a Joubert syndrome-associated protein module that regulates axonemal post-translational modifications and cilium stability

Latour

Weghe

Rusterholz

et al. 2019

Preprint

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“…The TOG domain array-containing proteins ch-TOG and CLASP are key regulators of cytoplasmic MTs (15). The cytoplasmic TOG array proteins have been extensively studied, however, the first TOG array protein that regulates ciliary MT, crescerin, has been reported only very recently (22). The number of TOG domains in each array differs.…”

Section: Discussionmentioning

confidence: 99%

“…Higher eukaryotic ch-TOG family members use a pentameric TOG domain array to promote MT polymerization, whereas CLASP members use a trimeric TOG domain array to stabilize MTs (15). Members of the newly described crescerin family contain four TOG domains and have been suggested to promote MT polymerization in vitro (22). Cep104 contains only one TOG domain, but the whole protein is dimeric in solution due to the presence of a coiled-coil region.…”

Section: Discussionmentioning

confidence: 99%

Biophysical and Structural Characterization of the Centriolar Protein Cep104 Interaction Network

Rezabkova

Kraatz

Akhmanova

et al. 2016

Journal of Biological Chemistry

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“…R402 residue facilitates dynein activity (Aiken, Moore, & Bates, 2018;Uchimura et al, 2015). Structural data suggests that V409 residue interacts with TOG domains (Das, Dickinson, Wood, Goldstein, & Slep, 2015). R422 residue lies in helix 12, which interacts with Tau/MAP2 (Al-Bassam, Ozer, Safer, Halpain, & Milligan, 2002;Löwe, Li, Downing, & Nogales, 2001).…”

Section: Disease-associated Mutant Alleles Generated In Yeast α-Tubmentioning

confidence: 99%

Tubulin mutations in brain development disorders: Why haploinsufficiency does not explain TUBA1A tubulinopathies

et al. 2019

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The neuronal cytoskeleton performs incredible feats during nervous system development. Extension of neuronal processes, migration, and synapse formation rely on the proper regulation of microtubules. Mutations that disrupt the primary α‐tubulin expressed during brain development, TUBA1A, are associated with a spectrum of human brain malformations. One model posits that TUBA1A mutations lead to a reduction in tubulin subunits available for microtubule polymerization, which represents a haploinsufficiency mechanism. We propose an alternative model for the majority of tubulinopathy mutations, in which the mutant tubulin polymerizes into the microtubule lattice to dominantly “poison” microtubule function. Nine distinct α‐tubulin and ten β‐tubulin genes have been identified in the human genome. These genes encode similar tubulin proteins, called isotypes. Multiple tubulin isotypes may partially compensate for heterozygous deletion of a tubulin gene, but may not overcome the disruption caused by missense mutations that dominantly alter microtubule function. Here, we describe disorders attributed to haploinsufficiency versus dominant negative mechanisms to demonstrate the hallmark features of each disorder. We summarize literature on mouse models that represent both knockout and point mutants in tubulin genes, with an emphasis on how these mutations might provide insight into the nature of tubulinopathy patient mutations. Finally, we present data from a panel of TUBA1A tubulinopathy mutations generated in yeast α‐tubulin that demonstrate that α‐tubulin mutants can incorporate into the microtubule network and support viability of yeast growth. This perspective on tubulinopathy mutations draws on previous studies and additional data to provide a fresh perspective on how TUBA1A mutations disrupt neurodevelopment.

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Crescerin uses a TOG domain array to regulate microtubules in the primary cilium

Cited by 62 publications

References 64 publications

ARMC9 and TOGARAM1 define a Joubert syndrome-associated protein module that regulates axonemal post-translational modifications and cilium stability

ARMC9 and TOGARAM1 define a Joubert syndrome-associated protein module that regulates axonemal post-translational modifications and cilium stability

Biophysical and Structural Characterization of the Centriolar Protein Cep104 Interaction Network

Tubulin mutations in brain development disorders: Why haploinsufficiency does not explain TUBA1A tubulinopathies

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