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REVIEW article
Front. Biophys.
Sec. Protein Structure and Dynamics
Volume 3 - 2025 | doi: 10.3389/frbis.2025.1560824
Decoding TBCK
Provisionally accepted- Florida State University, Tallahassee, United States
TBCK is an essential protein in neurodevelopment. Mutations in the TBCK gene are associated with TBCK Syndrome, a genetic neurological disorder characterized by global developmental delay. TBCK is an enigmatic multidomain protein that contains a pseudokinase domain, a TBC (Tre2-Bub2-Cdc16) domain, and a rhodanese-like domain. Emerging evidence increasingly links TBCK to multiple cellular processes, including mTOR signaling, autophagy, lysosomal function, and mitochondrial maintenance. This review consolidates recent advances in our understanding of TBCK, emphasizing comparative sequence analysis, structural modeling, and its cellular functions. Our analysis shows that both the protein kinase domain and the rhodanese-like domain likely lack catalytic activity and instead primarily function as scaffolds or regulatory domains. The TBC domain contains all the conserved residues, suggesting it may act as a GTPase-activating protein (GAP). These functional hypotheses provide a foundation for further investigations into TBCK's physiological and pathological roles.
Keywords: TBCK, protein kinase, TBC domain, TRE2-BUB2-CDC16 domain, Genetic disorder, Rhodanese domain
Received: 15 Jan 2025; Accepted: 14 Mar 2025.
Copyright: © 2025 Cagwin, Padgett, Lin and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wen Zhu, Florida State University, Tallahassee, United States
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