| Structural highlights
Disease
1433E_HUMAN Distal 17p13.3 microdeletion syndrome;17p13.3 microduplication syndrome;Miller-Dieker syndrome.
Function
1433E_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.
Publication Abstract from PubMed
Genetic screening technologies to identify and validate macromolecular interactions (MMIs) essential for complex pathways remain an important unmet need for systems biology and therapeutics development. Here, we use a library of peptides from diverse prokaryal genomes to screen MMIs promoting the nuclear relocalization of Forkhead Box O3 (FOXO3a), a tumor suppressor more frequently inactivated by post-translational modification than mutation. A hit peptide engages the 14-3-3 family of signal regulators through a phosphorylation-dependent interaction, modulates FOXO3a-mediated transcription, and suppresses cancer cell growth. In a crystal structure, the hit peptide occupies the phosphopeptide-binding groove of 14-3-3epsilon in a conformation distinct from its natural peptide substrates. A biophysical screen identifies drug-like small molecules that displace the hit peptide from 14-3-3epsilon, providing starting points for structure-guided development. Our findings exemplify "protein interference," an approach using evolutionarily diverse, natural peptides to rapidly identify, validate, and develop chemical probes against MMIs essential for complex cellular phenotypes.
Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library.,Emery A, Hardwick BS, Crooks AT, Milech N, Watt PM, Mithra C, Kumar V, Giridharan S, Sadasivam G, Mathivanan S, Sudhakar S, Bairy S, Bharatham K, Hurakadli MA, Prasad TK, Kamariah N, Muellner M, Coelho M, Torrance CJ, McKenzie GJ, Venkitaraman AR Cell Chem Biol. 2021 Nov 18;28(11):1602-1615.e9. doi: , 10.1016/j.chembiol.2021.05.009. Epub 2021 Jun 9. PMID:34111400[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Emery A, Hardwick BS, Crooks AT, Milech N, Watt PM, Mithra C, Kumar V, Giridharan S, Sadasivam G, Mathivanan S, Sudhakar S, Bairy S, Bharatham K, Hurakadli MA, Prasad TK, Kamariah N, Muellner M, Coelho M, Torrance CJ, McKenzie GJ, Venkitaraman AR. Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library. Cell Chem Biol. 2021 Nov 18;28(11):1602-1615.e9. PMID:34111400 doi:10.1016/j.chembiol.2021.05.009
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