TTLL10 is a protein polyglycylase that can modify nucleosome assembly protein 1

Ikegami, Koji; Horigome, Daisuke; Mukai, Masanori; Livnat, Itamar; MacGregor, Grant R.; Setou, Mitsutoshi

doi:10.1016/j.febslet.2008.02.079

Cited by 45 publications

(43 citation statements)

References 23 publications

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“…In D. melanogaster, DmTTLL3A mono-and polyglycylates the ␣-and the ␤-tubulin, whereas DmTTLL3B mono-and polyglycylates non-tubulin proteins (10). Notably, mammalian TTLL10 is also able to act as a bifunctional enzyme on nucleosome assembly proteins (8). The evidence that gTTLL3 is the only member of the giardial TTLL family clustering close to other mono-and polyglycylases and that G. duodenalis does not have a TTLL10 homolog protein (Ref.…”

Section: Discussionmentioning

confidence: 94%

“…Deglycylation of nuclear proteins, such as transcriptional or chromatin remodeling factors, might be responsible for the defect in encystation most clearly observed in the FLAG-gDIP2 transgenic line. It has been proposed that glycylation by TTLL10 of nucleosome assembly protein 1 (NAP1) in the mouse might modulate NAP1-histone interactions, thus inducing transcriptional repression during spermiogenesis (8). In D. melanogaster, depletion of DmTTLL3B protein results in several defects attributed to the potential lack of glycylation of its substrates, including chaperonins and motor proteins (10).…”

Section: Discussionmentioning

confidence: 99%

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Giardia Duodenalis 14-3-3 Protein Is Polyglycylated by a Tubulin Tyrosine Ligase-like Member and Deglycylated by Two Metallocarboxypeptidases

Lalle¹,

Camerini

Cecchetti

et al. 2011

Journal of Biological Chemistry

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The flagellated protozoan Giardia duodenalis is a parasite of the upper part of the small intestine of mammals, including humans, and an interesting biological model. Giardia harbors a single 14-3-3 isoform, a multifunctional protein family, that is modified at the C terminus by polyglycylation, an unusual post-translational modification consisting of the covalent addition of one or multiple glycines on the ␥-carboxyl groups of specific glutamic acids. Polyglycylation affects the intracellular localization of g14-3-3, as the shortening of the polyglycine chain is correlated with a partial relocalization of 14-3-3 inside the nuclei during encystation. In this work we demonstrate that the gTTLL3, a member of the tubulin tyrosine ligase-like family, is the enzyme responsible for the 14-3-3 polyglycylation. We also identify two metallopeptidases of the M20 family, here termed gDIP1 (giardial dipeptidase 1) and gDIP2, as enzymes able to shorten the g14-3-3 polyglycine tail both in vivo and in vitro. Finally, we show that the ectopic expression of gDIP2 alters the g14-3-3 localization and strongly hampers the cyst formation. In conclusion, we have identified a polyglycylase and two deglycylases that act in concert to modulate the stage-dependent glycylation status of the multifunctional regulatory g14-3-3 protein in G. duodenalis. The flagellated and binucleated protozoan Giardia duodenalis (synonymous of Giardia lamblia and Giardia intestinalis)is an extracellular parasite of the upper part of the small intestine of mammals, including humans, where it causes giardiasis, an acute enteritis (1). Besides its relevance for human and animal health, G. duodenalis is also a fascinating and simple eukaryotic organism with a minimalistic genomic and cellular organization that arouses a great interest as a biological model (2). In this perspective we have previously characterized the single giardial 14-3-3 (g14-3-3) isoform, a member of a small dimeric protein family ubiquitously conserved in eukaryotes (3, 4). The 14-3-3s are able to bind a wide range of proteins containing consensus binding motifs usually phosphorylated on serine or threonine, thus, regulating multiple cellular processes, i.e. the metabolism, cell cycle progression, signal transduction pathways, cell growth, and differentiation (5). We demonstrated that the g14-3-3 is modified in a peculiar fashion by the phosphorylation of Thr-214 and the polyglycylation of 4). The glycylation, first discovered at the C-terminal domain of ␣-and ␤-tubulin, is a post-translational modification consisting of the covalent addition of one or multiple glycines to the ␥-carboxyl groups of specific glutamic acids of target proteins (6, 7). Recently, polyglycylation has been also reported for several proteins, including the mammalian nucleosome assembly proteins (8 -10). Whereas the phosphorylation of g14-3-3 is a constitutive post-translational modification, the polyglycylation of the protein is regulated during the G. duodenalis life cycle with a remarkable reduction in the length...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Giardia Duodenalis 14-3-3 Protein Is Polyglycylated by a Tubulin Tyrosine Ligase-like Member and Deglycylated by Two Metallocarboxypeptidases

Lalle¹,

Camerini

Cecchetti

et al. 2011

Journal of Biological Chemistry

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“…This simple addition of a mere polypeptide that has no outstanding characteristic had made it difficult for researchers to anticipate the function of the modification. However, the roles of tubulin polyglycylation are now beginning to be unveiled, as TTLLs 3, 8, and 10 are identified as polyglycylation-performing enzymes, the polyglycylases (or glycine ligases) (Ikegami et al, 2008;Ikegami and Setou, 2009;Rogowski et al, 2009;Wloga et al, 2009b).…”

Section: Polyglycylationmentioning

confidence: 99%

Unique Post-Translational Modifications in Specialized Microtubule Architecture

Ikegami

Setou

2010

Cell Struct. Funct.

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ABSTACT.Microtubules (MTs) play specialized roles in a wide variety of cellular events, e.g. molecular transport, cell motility, and cell division. Specialized MT architectures, such as bundles, axonemes, and centrioles, underlie the function. The specialized function and highly organized structure depend on interactions with MT-binding proteins. MT-associated proteins (e.g. MAP1, MAP2, and tau), molecular motors (kinesin and dynein), plus-end tracking proteins (e.g. CLIP-170), and MT-severing proteins (e.g. katanin) interact with MTs. How can the MT-binding proteins know temporospatial information to associate with MTs and to properly play their roles? Post-translational modifications (PTMs) including detyrosination, polyglutamylation, and polyglycylation can provide molecular landmarks for the proteins. Recent efforts to identify modificationregulating enzymes (TTL, carboxypeptidase, polyglutamylase, polyglycylase) and to generate genetically manipulated animals enable us to understand the roles of the modifications. In this review, we present recent advances in understanding regulation of MT function, structure, and stability by PTMs.

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“…41 Mutation of Pgs1 (GTRGEO22) in ROSA22 mice has been associated with male sterility and neuronal defects. 7 Subsequent analysis of the these Pgs1-mutant mice has revealed a notable loss of polyglutamylation on a tubulin, 25 indicating that PGs1 is important for tubulin polyglutamylation. PGs1 lacks catalytic activity, but its localization at tubulin polyglutamylation sites in neurons, axonemes, and centrioles 46 suggests that it, like the fleer protein in zebrafish, may be involved in the regulation, localization, or transport of the larger polyglutamylase complex.…”

Section: Discussionmentioning

confidence: 99%

Tubulin Tyrosine Ligase–Like 1 Deficiency Results in Chronic Rhinosinusitis and Abnormal Development of Spermatid Flagella in Mice

et al. 2010

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Tubulin tyrosine ligase-like 1 (TTLL1) protein is a member of the tubulin tyrosine ligase superfamily of proteins that are involved in the posttranslational polyglutamylation of tubulin in axonemal microtubules within cilia and flagella. To investigate the physiological role of TTLL1, the authors generated mice with a gene trap mutation in the Ttll1 gene that provide confirmation in a mammalian model that polyglutamylation plays an important role in some ciliary and flagellar functions. For the first time, mice homozygous for the Ttll1 mutation exhibited accumulations of exudates in the nasal passages and sinuses, rhinosinusitis, otitis media, and male infertility. In homozygous mutant male mice, abnormal sperm morphology and function were characterized by shortened or absent flagella and immotility. Although homozygous mutant males were infertile, the females were fertile. These findings are consistent with a diagnosis of primary ciliary dyskinesia (PCD) resulting from ciliary dysfunction. They indicate that Ttll1 is essential for normal motility of respiratory cilia and the biogenesis and function of sperm flagella but that the defect does not result in the hydrocephalus or laterality defects often seen in other forms of PCD. The absence of early-onset lethal hydrocephalus in Ttll1-mutant mice may enable studies to evaluate the long-term effects of PCD in the respiratory system of mice. Although no mutations in the orthologous gene have been linked with PCD in humans, investigating the role of TTLL1 and polyglutamylation of tubulin in cilia and flagella should advance an understanding of the biogenesis and function of these organelles in mammals and have potential diagnostic and therapeutic applications.

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TTLL10 is a protein polyglycylase that can modify nucleosome assembly protein 1

Cited by 45 publications

References 23 publications

Giardia Duodenalis 14-3-3 Protein Is Polyglycylated by a Tubulin Tyrosine Ligase-like Member and Deglycylated by Two Metallocarboxypeptidases

Giardia Duodenalis 14-3-3 Protein Is Polyglycylated by a Tubulin Tyrosine Ligase-like Member and Deglycylated by Two Metallocarboxypeptidases

Unique Post-Translational Modifications in Specialized Microtubule Architecture

Tubulin Tyrosine Ligase–Like 1 Deficiency Results in Chronic Rhinosinusitis and Abnormal Development of Spermatid Flagella in Mice

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