Journal
SCIENCE
Volume 376, Issue 6595, Pages 815-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abn6020
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Funding
- NWO Vici grant [016.Vici.170.033]
- NWO ENW [OCENW.M20.324]
- Austrian Science Fund (FWF) [J 4448]
- NWO X-omics Initiative
- Leducq Foundation [20CVD01]
- ANR [20-CE16-0021]
- Lundbeck Foundation [R215-2015-4081]
- Novo Nordisk Foundation [NNF19OC0058504]
- Lundbeck Foundation [R215-2015-4081] Funding Source: researchfish
- Novo Nordisk Fonden [NNF19OC0058504] Funding Source: researchfish
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The detyrosination-tyrosination cycle is an important process implicated in cognitive, cardiac, and mitotic defects. This study identified an unannotated protein, MATCAP, as a component of this cycle, revealing its importance in brain formation.
The detyrosination-tyrosination cycle involves the removal and religation of the C-terminal tyrosine of a-tubulin and is implicated in cognitive, cardiac, and mitotic defects. The vasohibin-small vasohibin-binding protein (SVBP) complex underlies much, but not all, detyrosination. We used haploid genetic screens to identify an unannotated protein, microtubule associated tyrosine carboxypeptidase (MATCAP), as a remaining detyrosinating enzyme. X-ray crystallography and cryo-electron microscopy structures established MATCAP's cleaving mechanism, substrate specificity, and microtubule recognition. Paradoxically, whereas abrogation of tyrosine religation is lethal in mice, codeletion of MATCAP and SVBP is not. Although viable, defective detyrosination caused microcephaly, associated with proliferative defects during neurogenesis, and abnormal behavior. Thus, MATCAP is a missing component of the detyrosination-tyrosination cycle, revealing the importance of this modification in brain formation.
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