Tags

Type your tag names separated by a space and hit enter

Molecular Basis of the Mechanisms Controlling MASTL.
Mol Cell Proteomics. 2020 02; 19(2):326-343.MC

Abstract

The human MASTL (Microtubule-associated serine/threonine kinase-like) gene encodes an essential protein in the cell cycle. MASTL is a key factor preventing early dephosphorylation of M-phase targets of Cdk1/CycB. Little is known about the mechanism of MASTL activation and regulation. MASTL contains a non-conserved insertion of 550 residues within its activation loop, splitting the kinase domain, and making it unique. Here, we show that this non-conserved middle region (NCMR) of the protein is crucial for target specificity and activity. We performed a phosphoproteomic assay with different MASTL constructs identifying key phosphorylation sites for its activation and determining whether they arise from autophosphorylation or exogenous kinases, thus generating an activation model. Hydrogen/deuterium exchange data complements this analysis revealing that the C-lobe in full-length MASTL forms a stable structure, whereas the N-lobe is dynamic and the NCMR and C-tail contain few localized regions with higher-order structure. Our results indicate that truncated versions of MASTL conserving a cryptic C-Lobe in the NCMR, display catalytic activity and different targets, thus establishing a possible link with truncated mutations observed in cancer-related databases.

Authors+Show Affiliations

The Novo Nordisk Foundation Center for Protein Research, Protein Structure & Function Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.The Novo Nordisk Foundation Center for Protein Research, Protein Structure & Function Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.The Novo Nordisk Foundation Center for Protein Research, Proteomics Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.The Novo Nordisk Foundation Center for Protein Research, Protein Structure & Function Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.Protein Analysis Group, Department of Pharmacy, Faculty of Health and Medical Sciences, University of CopenhagenCopenhagen, Denmark.Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.The Novo Nordisk Foundation Center for Protein Research, Protein Structure & Function Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.The Novo Nordisk Foundation Center for Protein Research, Protein Structure & Function Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.The Novo Nordisk Foundation Center for Protein Research, Protein Structure & Function Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.Protein Analysis Group, Department of Pharmacy, Faculty of Health and Medical Sciences, University of CopenhagenCopenhagen, Denmark.The Novo Nordisk Foundation Center for Protein Research, Proteomics Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.The Novo Nordisk Foundation Center for Protein Research, Protein Structure & Function Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark guillermo.montoya@cpr.ku.dk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31852836

Citation

Hermida, Dario, et al. "Molecular Basis of the Mechanisms Controlling MASTL." Molecular & Cellular Proteomics : MCP, vol. 19, no. 2, 2020, pp. 326-343.
Hermida D, Mortuza GB, Pedersen AK, et al. Molecular Basis of the Mechanisms Controlling MASTL. Mol Cell Proteomics. 2020;19(2):326-343.
Hermida, D., Mortuza, G. B., Pedersen, A. K., Pozdnyakova, I., Nguyen, T. T. T. N., Maroto, M., Williamson, M., Ebersole, T., Cazzamali, G., Rand, K., Olsen, J. V., Malumbres, M., & Montoya, G. (2020). Molecular Basis of the Mechanisms Controlling MASTL. Molecular & Cellular Proteomics : MCP, 19(2), 326-343. https://doi.org/10.1074/mcp.RA119.001879
Hermida D, et al. Molecular Basis of the Mechanisms Controlling MASTL. Mol Cell Proteomics. 2020;19(2):326-343. PubMed PMID: 31852836.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular Basis of the Mechanisms Controlling MASTL. AU - Hermida,Dario, AU - Mortuza,Gulnahar B, AU - Pedersen,Anna-Kathrine, AU - Pozdnyakova,Irina, AU - Nguyen,Tam T T N, AU - Maroto,Maria, AU - Williamson,Michael, AU - Ebersole,Tasja, AU - Cazzamali,Giuseppe, AU - Rand,Kasper, AU - Olsen,Jesper V, AU - Malumbres,Marcos, AU - Montoya,Guillermo, Y1 - 2019/12/18/ PY - 2019/11/26/received PY - 2021/02/01/pmc-release PY - 2019/12/20/pubmed PY - 2019/12/20/medline PY - 2019/12/20/entrez KW - Kinases KW - cancer biology KW - cell cycle KW - mitosis KW - protein phosphatases SP - 326 EP - 343 JF - Molecular & cellular proteomics : MCP JO - Mol. Cell Proteomics VL - 19 IS - 2 N2 - The human MASTL (Microtubule-associated serine/threonine kinase-like) gene encodes an essential protein in the cell cycle. MASTL is a key factor preventing early dephosphorylation of M-phase targets of Cdk1/CycB. Little is known about the mechanism of MASTL activation and regulation. MASTL contains a non-conserved insertion of 550 residues within its activation loop, splitting the kinase domain, and making it unique. Here, we show that this non-conserved middle region (NCMR) of the protein is crucial for target specificity and activity. We performed a phosphoproteomic assay with different MASTL constructs identifying key phosphorylation sites for its activation and determining whether they arise from autophosphorylation or exogenous kinases, thus generating an activation model. Hydrogen/deuterium exchange data complements this analysis revealing that the C-lobe in full-length MASTL forms a stable structure, whereas the N-lobe is dynamic and the NCMR and C-tail contain few localized regions with higher-order structure. Our results indicate that truncated versions of MASTL conserving a cryptic C-Lobe in the NCMR, display catalytic activity and different targets, thus establishing a possible link with truncated mutations observed in cancer-related databases. SN - 1535-9484 UR - https://www.unboundmedicine.com/medline/citation/31852836/Molecular_Basis_of_the_Mechanisms_Controlling_MASTL_ L2 - http://www.mcponline.org/cgi/pmidlookup?view=long&pmid=31852836 DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.