Carboxyterminal post-translational modifications of tubulin (Homo sapiens)

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14, 16, 1811, 1510, 14, 16, 173, 4, 81, 2, 7, 9, 133, 185, 6, 12cytosolTTLL3,TTLL8,TTLL10VASH1 TUBB2B SVBP TTLL8 Microtubule protofilament AGBL5 TTLL9 TTLL2 Tubulin beta-8 chain-like protein TUBA1A TTLL12 TUBA1B VASH2 TUBB4A ADPTTLL3 TTLL1 H2OTUBA1B(1-450) TUBA3E TUBB4B Tubulin beta-8 chain-like protein Microtubule protofilament Polyglycylated microtubule protofilament AGBL1 TUBB2B TUBA3E(1-449) GTP LRRC49 CCPsAGBL2 TUBB2A TUBB1 alphaY-beta tubulindimerTUBA1C TUBA1C(1-448) TUBA3C/3D PolyglycylatedmicrotubuleTUBB1 TTLL11 TUBB4A TPGS1 GDP GlyGTP H2OTTLTUBB8 AGBL4 AGBL3 TTLL6 NICN1 TTLL10 TUBB2A TTLL5 Polyglutamyl microtubule protofilament PiL-GluTTLLsL-TyrTUBA1A(1-450) GDP TTLL7 Microtubule protofilament PolyglutamylatedmicrotubuleTPGS2 TTLL4 SVBP:VASH1,VASH2TUBB6 TUBB6 TUBB3 ADPAGTPBP1 MicrotubuleTUBA3C/3D(1-449) ATPTUBB3 detyr-alphatubulin:betatubulinTTLL13P TUBB8 polyglutamylasecomplexTUBB4B


Description

Tubulins fold into compact globular domains with less structured carboxyterminal tails. These tails vary in sequence between tubulin isoforms and are exposed on the surfaces of microtubules. They can undergo a variety of posttranslational modifications, including the attachment and removal of polyglutamate chains and in the case of alpha-tunulins the loss and reattachment of a terminal tyrosine (Tyr) residue. These modifications are associated with changes in the rigidity and stability of microtubules (Song & Brady 2015; Yu et al. 2015).
Mutations affecting these modification processes can have severe effects on phenotype (e.g., Ikegami et al. 2007). Nevertheless, the precise molecular mechanisms by which these changes in tubulin structure modulate its functions remain unclear, so these modification processes are simply annotated here as a series of chemical transformations of tubulins. View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8955332
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Bibliography

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  1. Kalinina E, Biswas R, Berezniuk I, Hermoso A, Aviles FX, Fricker LD.; ''A novel subfamily of mouse cytosolic carboxypeptidases.''; PubMed Europe PMC Scholia
  2. Tort O, Tanco S, Rocha C, Bièche I, Seixas C, Bosc C, Andrieux A, Moutin MJ, Avilés FX, Lorenzo J, Janke C.; ''The cytosolic carboxypeptidases CCP2 and CCP3 catalyze posttranslational removal of acidic amino acids.''; PubMed Europe PMC Scholia
  3. Janke C, Rogowski K, Wloga D, Regnard C, Kajava AV, Strub JM, Temurak N, van Dijk J, Boucher D, van Dorsselaer A, Suryavanshi S, Gaertig J, Eddé B.; ''Tubulin polyglutamylase enzymes are members of the TTL domain protein family.''; PubMed Europe PMC Scholia
  4. Ikegami K, Mukai M, Tsuchida J, Heier RL, Macgregor GR, Setou M.; ''TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites.''; PubMed Europe PMC Scholia
  5. Wloga D, Webster DM, Rogowski K, Bré MH, Levilliers N, Jerka-Dziadosz M, Janke C, Dougan ST, Gaertig J.; ''TTLL3 Is a tubulin glycine ligase that regulates the assembly of cilia.''; PubMed Europe PMC Scholia
  6. Rogowski K, Juge F, van Dijk J, Wloga D, Strub JM, Levilliers N, Thomas D, Bré MH, Van Dorsselaer A, Gaertig J, Janke C.; ''Evolutionary divergence of enzymatic mechanisms for posttranslational polyglycylation.''; PubMed Europe PMC Scholia
  7. Rodriguez de la Vega M, Sevilla RG, Hermoso A, Lorenzo J, Tanco S, Diez A, Fricker LD, Bautista JM, Avilés FX.; ''Nna1-like proteins are active metallocarboxypeptidases of a new and diverse M14 subfamily.''; PubMed Europe PMC Scholia
  8. van Dijk J, Rogowski K, Miro J, Lacroix B, Eddé B, Janke C.; ''A targeted multienzyme mechanism for selective microtubule polyglutamylation.''; PubMed Europe PMC Scholia
  9. Kimura Y, Kurabe N, Ikegami K, Tsutsumi K, Konishi Y, Kaplan OI, Kunitomo H, Iino Y, Blacque OE, Setou M.; ''Identification of tubulin deglutamylase among Caenorhabditis elegans and mammalian cytosolic carboxypeptidases (CCPs).''; PubMed Europe PMC Scholia
  10. Aillaud C, Bosc C, Peris L, Bosson A, Heemeryck P, Van Dijk J, Le Friec J, Boulan B, Vossier F, Sanman LE, Syed S, Amara N, Couté Y, Lafanechère L, Denarier E, Delphin C, Pelletier L, Humbert S, Bogyo M, Andrieux A, Rogowski K, Moutin MJ.; ''Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation.''; PubMed Europe PMC Scholia
  11. Prota AE, Magiera MM, Kuijpers M, Bargsten K, Frey D, Wieser M, Jaussi R, Hoogenraad CC, Kammerer RA, Janke C, Steinmetz MO.; ''Structural basis of tubulin tyrosination by tubulin tyrosine ligase.''; PubMed Europe PMC Scholia
  12. Ikegami K, Horigome D, Mukai M, Livnat I, MacGregor GR, Setou M.; ''TTLL10 is a protein polyglycylase that can modify nucleosome assembly protein 1.''; PubMed Europe PMC Scholia
  13. Rogowski K, van Dijk J, Magiera MM, Bosc C, Deloulme JC, Bosson A, Peris L, Gold ND, Lacroix B, Bosch Grau M, Bec N, Larroque C, Desagher S, Holzer M, Andrieux A, Moutin MJ, Janke C.; ''A family of protein-deglutamylating enzymes associated with neurodegeneration.''; PubMed Europe PMC Scholia
  14. Yu I, Garnham CP, Roll-Mecak A.; ''Writing and Reading the Tubulin Code.''; PubMed Europe PMC Scholia
  15. Deans NL, Allison RD, Purich DL.; ''Steady-state kinetic mechanism of bovine brain tubulin: tyrosine ligase.''; PubMed Europe PMC Scholia
  16. Song Y, Brady ST.; ''Post-translational modifications of tubulin: pathways to functional diversity of microtubules.''; PubMed Europe PMC Scholia
  17. Argarana CE, Barra HS, Caputto R.; ''Tubulinyl-tyrosine carboxypeptidase from chicken brain: properties and partial purification.''; PubMed Europe PMC Scholia
  18. Ikegami K, Heier RL, Taruishi M, Takagi H, Mukai M, Shimma S, Taira S, Hatanaka K, Morone N, Yao I, Campbell PK, Yuasa S, Janke C, Macgregor GR, Setou M.; ''Loss of alpha-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114916view16:43, 25 January 2021ReactomeTeamReactome version 75
113361view11:43, 2 November 2020ReactomeTeamReactome version 74
112570view15:54, 9 October 2020ReactomeTeamReactome version 73
101484view11:34, 1 November 2018ReactomeTeamreactome version 66
101021view21:14, 31 October 2018ReactomeTeamreactome version 65
100556view19:48, 31 October 2018ReactomeTeamreactome version 64
100104view16:33, 31 October 2018ReactomeTeamreactome version 63
99654view15:04, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99256view12:45, 31 October 2018ReactomeTeamreactome version 62
93418view11:23, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
AGBL1 ProteinQ96MI9 (Uniprot-TrEMBL)
AGBL2 ProteinQ5U5Z8 (Uniprot-TrEMBL)
AGBL3 ProteinQ8NEM8 (Uniprot-TrEMBL)
AGBL4 ProteinQ5VU57 (Uniprot-TrEMBL)
AGBL5 ProteinQ8NDL9 (Uniprot-TrEMBL)
AGTPBP1 ProteinQ9UPW5 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
CCPsComplexR-HSA-8866075 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
GlyMetaboliteCHEBI:57305 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
L-TyrMetaboliteCHEBI:58315 (ChEBI)
LRRC49 ProteinQ8IUZ0 (Uniprot-TrEMBL)
Microtubule protofilament R-HSA-8982424 (Reactome)
MicrotubuleComplexR-HSA-190599 (Reactome)
NICN1 ProteinQ9BSH3 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)
Polyglutamyl microtubule protofilament R-HSA-8867460 (Reactome)
Polyglutamylated microtubuleComplexR-HSA-8982724 (Reactome)
Polyglycylated microtubuleComplexR-HSA-8982726 (Reactome)
Polyglycylated microtubule protofilament R-HSA-8867406 (Reactome)
SVBP ProteinQ8N300 (Uniprot-TrEMBL)
SVBP:VASH1,VASH2ComplexR-HSA-9701922 (Reactome)
TPGS1 ProteinQ6ZTW0 (Uniprot-TrEMBL)
TPGS2 ProteinQ68CL5 (Uniprot-TrEMBL)
TTLL1 ProteinO95922 (Uniprot-TrEMBL)
TTLL10 ProteinQ6ZVT0 (Uniprot-TrEMBL)
TTLL11 ProteinQ8NHH1 (Uniprot-TrEMBL)
TTLL12 ProteinQ14166 (Uniprot-TrEMBL)
TTLL13P ProteinA6NNM8 (Uniprot-TrEMBL)
TTLL2 ProteinQ9BWV7 (Uniprot-TrEMBL)
TTLL3 ProteinQ9Y4R7 (Uniprot-TrEMBL)
TTLL3,TTLL8,TTLL10ComplexR-HSA-8867449 (Reactome)
TTLL4 ProteinQ14679 (Uniprot-TrEMBL)
TTLL5 ProteinQ6EMB2 (Uniprot-TrEMBL)
TTLL6 ProteinQ8N841 (Uniprot-TrEMBL)
TTLL7 ProteinQ6ZT98 (Uniprot-TrEMBL)
TTLL8 ProteinA6PVC2 (Uniprot-TrEMBL)
TTLL9 ProteinQ3SXZ7 (Uniprot-TrEMBL)
TTLLsComplexR-HSA-8865765 (Reactome)
TTLProteinQ8NG68 (Uniprot-TrEMBL)
TUBA1A ProteinQ71U36 (Uniprot-TrEMBL)
TUBA1A(1-450) ProteinQ71U36 (Uniprot-TrEMBL)
TUBA1B ProteinP68363 (Uniprot-TrEMBL)
TUBA1B(1-450) ProteinP68363 (Uniprot-TrEMBL)
TUBA1C ProteinQ9BQE3 (Uniprot-TrEMBL)
TUBA1C(1-448) ProteinQ9BQE3 (Uniprot-TrEMBL)
TUBA3C/3D R-HSA-9617118 (Reactome)
TUBA3C/3D(1-449) R-HSA-9617147 (Reactome)
TUBA3E ProteinQ6PEY2 (Uniprot-TrEMBL)
TUBA3E(1-449) ProteinQ6PEY2 (Uniprot-TrEMBL)
TUBB1 ProteinQ9H4B7 (Uniprot-TrEMBL)
TUBB2A ProteinQ13885 (Uniprot-TrEMBL)
TUBB2B ProteinQ9BVA1 (Uniprot-TrEMBL)
TUBB3 ProteinQ13509 (Uniprot-TrEMBL)
TUBB4A ProteinP04350 (Uniprot-TrEMBL)
TUBB4B ProteinP68371 (Uniprot-TrEMBL)
TUBB6 ProteinQ9BUF5 (Uniprot-TrEMBL)
TUBB8 ProteinQ3ZCM7 (Uniprot-TrEMBL)
Tubulin beta-8 chain-like protein ProteinA6NNZ2 (Uniprot-TrEMBL)
VASH1 ProteinQ7L8A9 (Uniprot-TrEMBL)
VASH2 ProteinQ86V25 (Uniprot-TrEMBL)
alphaY-beta tubulin dimerComplexR-HSA-8955726 (Reactome)
detyr-alpha

tubulin:beta

tubulin
ComplexR-HSA-8955574 (Reactome)
polyglutamylase complexComplexR-HSA-8955345 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-8865774 (Reactome)
ADPArrowR-HSA-8867370 (Reactome)
ADPArrowR-HSA-8955706 (Reactome)
ADPArrowR-HSA-8955869 (Reactome)
ATPR-HSA-8865774 (Reactome)
ATPR-HSA-8867370 (Reactome)
ATPR-HSA-8955706 (Reactome)
ATPR-HSA-8955869 (Reactome)
CCPsmim-catalysisR-HSA-8866105 (Reactome)
GlyR-HSA-8867370 (Reactome)
H2OR-HSA-8866105 (Reactome)
H2OR-HSA-8955712 (Reactome)
L-GluArrowR-HSA-8866105 (Reactome)
L-GluR-HSA-8865774 (Reactome)
L-GluR-HSA-8955869 (Reactome)
L-TyrArrowR-HSA-8955712 (Reactome)
L-TyrR-HSA-8955706 (Reactome)
MicrotubuleArrowR-HSA-8866105 (Reactome)
MicrotubuleR-HSA-8865774 (Reactome)
MicrotubuleR-HSA-8867370 (Reactome)
MicrotubuleR-HSA-8955869 (Reactome)
PiArrowR-HSA-8865774 (Reactome)
PiArrowR-HSA-8867370 (Reactome)
PiArrowR-HSA-8955706 (Reactome)
PiArrowR-HSA-8955869 (Reactome)
Polyglutamylated microtubuleArrowR-HSA-8865774 (Reactome)
Polyglutamylated microtubuleArrowR-HSA-8955869 (Reactome)
Polyglutamylated microtubuleR-HSA-8866105 (Reactome)
Polyglycylated microtubuleArrowR-HSA-8867370 (Reactome)
R-HSA-8865774 (Reactome) Tubulin is modified by glutamylation and glycylation, the additon of peptide branches made of glutamyl or glycyl residues respectively, which are attached to the gamma-carboxyl group of glutamic acids within the C-terminal tail domains of alpha- and beta-tubulin. Glutamylation, the most prevalent tubulin posttranslational modification, marks stable microtubules and regulates recruitment and activity of microtubule-interacting proteins. Hyperglutamylation in Purkinje cell degeneration (pcd) mice leads to neurodegeneration (Rogowski et al. 2010).

Nine enzymes of the tubulin tyrosine ligase-like (TTLL) family catalyze glutamylation (Garhnam & Roll-Mecak 2012, Garnham et al. 2015). TTLLs can have a preference for either alpha- or beta-tubulin, although many are able to modify either (Janke et al. 2005, Ikegami et al. 2006, van Dijk et al. 2007). Initial characterization of the mouse TTLL family showed that TTLL1, 5, 6, 11, and 13 preferentially poly-glutamylate alpha-tubulin, while TTLL4 and 7 prefer beta-tubulin. While TTLL1 has a preference for alpha-tubulin (Janke et al. 2005), TTLL1 knockout mice displayed decreased glutamylation on alpha- and beta-tubulin (Ikegami et al. 2010). The molecular determinants for specificity are poorly understood and specificity can differ between organisms, preventing an unambiguous classification of TTLLs by their alpha/beta preference. TTLL4, 5, and 7 have been described as initiases, adding a branched glutamic acid to the tubulin tail, while TTLL6, 11, and 13 were suggested to be elongases, adding poly-Glu chains of variable lengths to the branched glutamic acid (Garhnam & Roll-Mecak 2012). The specificity of mammalian TTLL2, 9, and TTLL12 are unknown.

TTLL3, 8, and 10 are glycylases that glycate rather than glutamylate tubulin (Ikegami et al. 2008, Ikegami & Setou 2009, Rogowski et al. 2009, Wloga et al. 2009), with TTLL3 and 8 serving as initiases, and TTLL10 serving as an elongase.

TTLL7, the most abundant glutamylase in neurons, modifies both alpha- and beta-tubulin tail peptides in isolation but shows a preference for beta-tubulin when presented with microtubules. TTLL7 catalyzes the initiatial glutamylation of Beta-tubulin glutamates at multiple internal positions in the Beta-tail, and also the addition of subsequent glutamates to existing branched glutamates (Mukai et al. 2009).
R-HSA-8866105 (Reactome) Cytosolic carboxypeptidases (CCPs) catalyze the removal of glutamate residues from the C-terminal tails of both alpha- and beta-tubulin. These glutamate residues are either enzymatically added in the polyglutamylation reaction, or gene-encoded glutamate residues are removed from alpha-tubulin after detyrosination to generate delta2-tubulin (Kimura et al. 2010, Rogowski et al. 2010). CCPs are members of the MC clan, M14 family, subfamily M14D of metallopeptidases (Kalinina et al. 2007, Rodriguez de la Vega et al. 2007). Mouse Ccp1, 2, 3, 4, and 6 are functionally homologous and remove linearly added glutamates from tubulin (alpha-peptide bonds), while Ccp5 specifically removes branching-point glutamates (gamma-peptide bonds) which are generated as first step of the polyglutamylation reaction (Rogowski et al. 2010; Tort et al. 2014). The catalytic activities of the human proteins are inferred from the properties of their mouse homologues and limited studies of human proteins expressed in cultured cells (Rogowski et al. 2010). In this event polyglutamylation is arbitrarily shown on only one tubulin protofilament within the polyglutamylated microtubule.
R-HSA-8867370 (Reactome) Tubulin is modified by glutamylation and glycylation, the additon of peptide branches made of glutamyl or glycyl residues respectively, which are attached to the gamma-carboxyl group of glutamic acids within the C-terminal tail domains of alpha- and beta-tubulin. They are added by members of the tubulin tyrosine ligase (TTL family). TTLL3, 8, and 10 are glycylases (Ikegami et al. 2008, Ikegami and Setou, 2009; Rogowski et al. 2009; Wloga et al. 2009) with TTLL3 and 8 serving as initiases, and TTLL10 serving as an elongase. In this event polyglycation is arbitrarily shown on only one tubulin protofilament within the microtubule.
R-HSA-8955706 (Reactome) TTL (tubulin tyrosine ligase) ligates tyrosine (L-Tyr) to the carboxy terminus of the alpha-tubulin subunit of an alpha tubulin:beta tubulin dimer in an ATP-dependent reaction. Human TTL has not been characterized in detail; the reaction mechanism annotated here has been worked out with bovine proteins (Deans et al. 1992), and structural studies with chicken proteins demonstrate the basis of the enzyme's specificity for the carboxy terminus of tubulin alpha chains (Prota et al. 2013).
R-HSA-8955712 (Reactome) TTCP (tubulinyl-tyrosine carboxypeptidase) hydrolyzes the terminal L-Tyr residue from the alpha-tubulin subunit of an alpha tubulin:beta tubulin dimer to yield delY-alpha tubulin and L-tyrosine (L-Tyr). Although TTCP enzyme has not been purified from any species, studies of material partially purified from chicken brain have allowed its activity to be defined and distinguished from those of widely expressed carboxypeptidases with broader substrate specificities (Argarana et al. 1980). This reaction is known to occur in humans (Song & Brody 2015; Yu et al. 2015) and its properties have been inferred from those of its chicken counterpart.
R-HSA-8955869 (Reactome) Polyglutamylase complex polyglutamylates alpha subunits of tubulin in the brain. The complex contains TTLL1 (Tubulin tyrosine ligase-like 1) protein. The human complex has not been characterized experimentally. Its organization and function have been inferred from biochemical and genetic studies of its mouse counterpart. The mouse complex has been isolated and four additional protein components have been identified (Janke et al. 2005). A mouse mutation that disrupts one of these, Tpgs1, is associated with failure of polyglytamylation of alpha-chains in microtubules (Ikegami et al. 2007). In this event polyglutamylation is arbitrarily shown on only one tubulin protofilament within the microtubule.
SVBP:VASH1,VASH2mim-catalysisR-HSA-8955712 (Reactome)
TTLL3,TTLL8,TTLL10mim-catalysisR-HSA-8867370 (Reactome)
TTLLsmim-catalysisR-HSA-8865774 (Reactome)
TTLmim-catalysisR-HSA-8955706 (Reactome)
alphaY-beta tubulin dimerArrowR-HSA-8955706 (Reactome)
alphaY-beta tubulin dimerR-HSA-8955712 (Reactome)
detyr-alpha

tubulin:beta

tubulin
ArrowR-HSA-8955712 (Reactome)
detyr-alpha

tubulin:beta

tubulin
R-HSA-8955706 (Reactome)
polyglutamylase complexmim-catalysisR-HSA-8955869 (Reactome)
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