Abstract
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | eabn6020 |
| Tidsskrift | Science |
| Vol/bind | 376 |
| Udgave nummer | 6595 |
| ISSN | 0036-8075 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:We thank members of the Brummelkamp group for helpful discussions and critical reading of the manuscript and members of the Perrakis and Sixma group (in particular, A. Murachelli and S. Bruekner) for discussions about cryo-EM data processing. We also thank the NKI Bioimaging, Flow cytometry, Genomics Core, Protein, Animal, cryo-EM, Research High Performance Computing (RHPC), MRI scanning, and experimental animal pathology NKI facilities for technical support, and in particular X. Guo (cryo-EM) and N. de Wit (MRI). The cryo-EM work benefited from access to the Netherlands Centre for Electron Nanoscopy (NeCEN) at Leiden University, an Instruct-ERIC centre, with assistance from W. E. M. Noteborn; financial support was provided by the Netherlands Electron Microscopy Infrastructure (NEMI). We acknowledge the Paul Scherrer Institut, Villigen, Switzerland, for provision of synchrotron radiation beamtime for the x-ray work at beamline, PXIII; SFR Biosciences (UAR3444/CNRS, US8/Inserm, ENS de Lyon, UCBL) and the ANIRA-PBES facility for help with the generation of SVBP mice; and the Advanced Light Microscopy Facility of the Medical School at the University of Patras for imaging support. We thank C. Nikolaou for advice on statistics. This work was supported by NWO Vici grant 016. Vici.170.033 to T.R.B.; A.P. and T.R.B. are Oncode investigators (https://www.oncode.nl) and receive funding from NWO ENW (OCENW.M20.324). L.L. was supported by the Austrian Science Fund (FWF):[J 4448]. O.B.B. is supported by the NWO X-omics Initiative. M.-J.M. is supported by the Leducq Foundation (20CVD01) and ANR (20-CE16-0021). M.B. is supported by the Lundbeck Foundation (R215-2015-4081) and the Novo Nordisk Foundation (NNF19OC0058504). This work benefited from access to the NKI Protein Facility and to NeCEN, both Instruct-ERIC centres.
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