FNIP1

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.^[5] FNIP1 acts as a scaffold to load FLCN onto Hsp90.^[5][6] FNIP1 is also involved in chaperoning of both kinase and non-kinase clients.

FNIP1
Identifiers
Aliases	FNIP1, folliculin interacting protein 1, IMD93
External IDs	OMIM: 610594; MGI: 2444668; HomoloGene: 28173; GeneCards: FNIP1; OMA:FNIP1 - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q31.1 Start 131,641,714 bp[1] End 131,797,017 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B1.3 Start 54,329,025 bp[2] End 54,409,061 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cardiac muscle tissue of right atrium myocardium of left ventricle synovial membrane Skeletal muscle tissue of rectus abdominis corpus callosum pancreatic epithelial cell vastus lateralis muscle pancreatic ductal cell deltoid muscle Achilles tendon Top expressed in intercostal muscle soleus muscle myocardium of ventricle iris spermatocyte calvaria stroma of bone marrow gastrocnemius muscle lobe of cerebellum Region I of hippocampus proper More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding guanyl-nucleotide exchange factor activity ATPase inhibitor activity chaperone binding Cellular component cytoplasm Biological process regulation of protein phosphorylation regulation of pro-B cell differentiation cellular response to starvation negative regulation of TOR signaling negative regulation of cysteine-type endopeptidase activity involved in apoptotic process positive regulation of protein phosphorylation negative regulation of transcription by RNA polymerase II TOR signaling positive regulation of B cell apoptotic process positive regulation of protein-containing complex assembly immature B cell differentiation positive regulation of peptidyl-serine phosphorylation mitochondrion organization TORC1 signaling negative regulation of mitochondrion organization negative regulation of TORC1 signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 96459 216742 Ensembl ENSG00000217128 ENSMUSG00000035992 UniProt Q8TF40 Q68FD7 RefSeq (mRNA) NM_133372 NM_001008738 NM_001346113 NM_001346114 NM_173753 RefSeq (protein) NP_001008738 NP_001333042 NP_001333043 NP_588613 NP_776114 Location (UCSC) Chr 5: 131.64 – 131.8 Mb Chr 11: 54.33 – 54.41 Mb PubMed search [3] [4]
Wikidata
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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.^[7] 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.^[8] 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.^[5]

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.^[9] O-GlcNAcylation antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 ubiquitination and proteasomal degradation.^[9] Post-translational regulation of FNIP1 creates a rheostat for the molecular chaperone Hsp90.^[9]

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.^[10][11][12]

References

1. GRCh38: Ensembl release 89: ENSG00000217128 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000035992 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, et al. (June 2016). "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding". Nature Communications. 7: 12037. Bibcode:2016NatCo...712037W. doi:10.1038/ncomms12037. PMC 4931344. PMID 27353360.
6. Sager RA, Woodford MR, Mollapour M (December 2018). "The mTOR Independent Function of Tsc1 and FNIPs". Trends in Biochemical Sciences. 43 (12): 935–937. doi:10.1016/j.tibs.2018.09.018. PMC 6324182. PMID 30361061.
7. Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, et al. (June 2016). "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding". Nature Communications. 7: 12037. Bibcode:2016NatCo...712037W. doi:10.1038/ncomms12037. PMC 4931344. PMID 27353360.
8. Neckers L, Blagg B, Haystead T, Trepel JB, Whitesell L, Picard D (July 2018). "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. doi:10.1007/s12192-018-0877-2. PMC 6045531. PMID 29392504.
9. Sager RA, Woodford MR, Backe SJ, Makedon AM, Baker-Williams AJ, DiGregorio BT, et al. (January 2019). "Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90". Cell Reports. 26 (5): 1344–1356.e5. doi:10.1016/j.celrep.2019.01.018. PMC 6370319. PMID 30699359.
10. Siggs OM, Stockenhuber A, Deobagkar-Lele M, Bull KR, Crockford TL, Kingston BL, et al. (June 2016). "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. Bibcode:2016PNAS..113E3706S. doi:10.1073/pnas.1607592113. PMC 4932993. PMID 27303042.
11. Baba M, Keller JR, Sun HW, Resch W, Kuchen S, Suh HC, et al. (August 2012). "The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development". Blood. 120 (6): 1254–1261. doi:10.1182/blood-2012-02-410407. PMC 3418720. PMID 22709692.
12. Park H, Staehling K, Tsang M, Appleby MW, Brunkow ME, Margineantu D, et al. (May 2012). "Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development". Immunity. 36 (5): 769–781. doi:10.1016/j.immuni.2012.02.019. PMC 3361584. PMID 22608497.