Biology:FNIP1
 Generic protein structure example |
Folliculin-interacting protein 1 (FNIP1) functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 (heat shock protein-90) and decelerates its chaperone cycle.[1] FNIP1 acts as a scaffold to load FLCN onto Hsp90.[1][2] FNIP1 is also involved in chaperoning of both kinase and non-kinase clients.
Co-chaperone function
FNIP1 does not have any known functional domains; however, based on amino acid sequence alignments, conserved regions were identified and named as A–D. The C-terminal domain of FNIP1 (amino acids 929–1,166 or fragment D) preferentially interacts with the middle domain of Hsp90. This fragment and the full-length FNIP1 are potent inhibitors/decelerator of Hsp90 ATPase activity.[3] Small-molecule inhibitors that target the nucleotide-binding pocket of the N-terminal domain of Hsp90 also inhibit its ATPase activity and lead to degradation of the client proteins.[4] However, FNIP1-mediated inhibition of Hsp90 ATPase activity appears to decelerate the chaperone cycle, not inhibit it completely, as overexpression of FNIP1 stabilizes and activates client proteins. This can also be reversed by the co-chaperone Aha1, which is the activator of the Hsp90 ATPase function and competes with FNIP1 for binding to Hsp90.[1]
Post-translational regulation
Casein-kinase-2 mediated sequential phosphorylation of the co-chaperone FNIP1 leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients.[5] O-GlcNAcylation antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 ubiquitination and proteasomal degradation.[5] Post-translational regulation of FNIP1 creates a rheostat for the molecular chaperone Hsp90.[5]
Clinical significance
Mutation of FNIP1 in mice causes a deficiency of B cells, and cardiomyopathy, with FNIP1 thought to act as a negative regulator of AMPK.[6][7][8]
References
- ↑ 1.0 1.1 1.2 "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding". Nature Communications 7: 12037. June 2016. doi:10.1038/ncomms12037. PMID 27353360. Bibcode: 2016NatCo...712037W.
- ↑ "The mTOR Independent Function of Tsc1 and FNIPs". Trends in Biochemical Sciences 43 (12): 935–937. December 2018. doi:10.1016/j.tibs.2018.09.018. PMID 30361061.
- ↑ "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding". Nature Communications 7: 12037. June 2016. doi:10.1038/ncomms12037. PMID 27353360. Bibcode: 2016NatCo...712037W.
- ↑ "Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development". Cell Stress & Chaperones 23 (4): 467–482. July 2018. doi:10.1007/s12192-018-0877-2. PMID 29392504.
- ↑ 5.0 5.1 5.2 "Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90". Cell Reports 26 (5): 1344–1356.e5. January 2019. doi:10.1016/j.celrep.2019.01.018. PMID 30699359.
- ↑ "Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity". Proceedings of the National Academy of Sciences of the United States of America 113 (26): E3706–E3715. June 2016. doi:10.1073/pnas.1607592113. PMID 27303042. Bibcode: 2016PNAS..113E3706S.
- ↑ "The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development". Blood 120 (6): 1254–1261. August 2012. doi:10.1182/blood-2012-02-410407. PMID 22709692.
- ↑ "Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development". Immunity 36 (5): 769–781. May 2012. doi:10.1016/j.immuni.2012.02.019. PMID 22608497.
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