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UniProt release 2018_09

Published October 10, 2018

Headline

Tubulin code: a long sought-after player identified

In eukaryotes, the cytoskeleton helps cells maintain their shape and internal organization, and provides mechanical support that enables cells to carry out essential functions, like division and movement. It is made of filamentous proteins, microtubules being the largest type of cytoskeletal filament. Microtubules are dynamically assembled from alpha-tubulin and beta-tubulin heterodimers, creating specific structures adapted to the cell’s needs, structures that can be as different from each other as a cilium can be from a mitotic spindle. How is this variety achieved using the same highly conserved building blocks? Part of the answer lies in the so-called 'tubulin code' which involves not only the differential expression of alpha-and beta-tubulin genes (tubulin isotypes), but also a plethora of post-translational modifications (PTMs). Tubulins have a globular core and a more variable C-terminal tail that is exposed at the microtubule surface, where many PTMs occur. One of first PTMs to be reported, back in the 70s, was C-terminal reversible detyrosination, which occurs on most alpha-, but not beta-, tubulins. The enzyme catalyzing the addition of tyrosine, tubulin-tyrosine ligase or TTL, was identified not long after, but the carboxypeptidase responsible for tubulin detyrosination remained elusive until recently.

Aillaud et al. tackled the problem by developing an irreversible inhibitor of tubulin carboxypeptidase activity, followed by mass spectrometry analysis of the inhibitor targets. Nieuwenhuis et al. performed gene-trapping mutagenesis in a haploid human cell line aimed at regulators of tubulin detyrosination. Both groups identified vasohibin-1 (VASH1) and 2 (VASH2) as the major alpha-tubulin-specific carboxypeptidases. Vasohibins were formerly predicted to have a protease fold, but their enzymatic activity had not been investigated. Actually, both enzymes show low carboxypeptidase activity when assayed on their own. Full activity requires the formation of a complex with another protein, called small vasohibin-binding protein, or SVBP. This may explain why previous attempts to identify tubulin carboxypeptidase have failed. SVBP-VASH complexes act preferentially on polymerized tubulins. When microtubules disassemble, TTL adds back a tyrosine residue at the C-terminus and the tubulin detyrosination/tyrosination cycle is closed.

The physiological importance of detyrosination has to be investigated. SVBP or vasohibin knockdown in mouse hippocampal neurons results in delayed axonal differentiation. In embryos, it affects neuronal migration during brain cortex differentiation. However, mice lacking VASH1 or VASH2 do not exhibit a dramatic phenotype. It should also be noted that vasohibin depletion in cells could not completely abolish activity, suggesting the existence of yet another enzyme.

The VASH1 and VASH2 protein entries have been updated and are now available in UniProtKB/Swiss-Prot.

Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

Deleted diseases

  • Alport syndrome, with macrothrombocytopenia
  • Bannayan-Riley-Ruvalcaba syndrome
  • Cowden syndrome 2
  • Cowden syndrome 3
  • Epstein syndrome
  • Fechtner syndrome
  • Macrothrombocytopenia and progressive sensorineural deafness
  • Sebastian syndrome

Changes to the controlled vocabulary for PTMs

New terms for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):

  • (2S)-4-hydroxyleucine
  • (3S)-3-hydroxylysine
  • (4S)-4,5-dihydroxyleucine
  • 2-hydroxyproline
  • 3',4',5'-trihydroxyphenylalanine
  • 4-hydroxylysine

Modified term for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):

  • Hydroxylated arginine -> Hydroxyarginine

UniProt website news

Deprecation of legacy REST URLs /batch and /mapping – please replace by /uploadlists

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The obsolete URL paths /batch and /mapping have been deprecated and are no longer supported as of release 2018_09.

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