FNIP1

Last updated
FNIP1
Identifiers
Aliases FNIP1 , folliculin interacting protein 1, IMD93
External IDs OMIM: 610594 MGI: 2444668 HomoloGene: 28173 GeneCards: FNIP1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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
View/Edit Human View/Edit Mouse

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.

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Hsp70</span> Heat shock protein

The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.

<span class="mw-page-title-main">Hsp90</span> Heat shock proteins with a molecular mass around 90kDa

Hsp90 is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.

<span class="mw-page-title-main">Hop (protein)</span>

Hop, occasionally written HOP, is an abbreviation for Hsp70-Hsp90 Organizing Protein. It functions as a co-chaperone which reversibly links together the protein chaperones Hsp70 and Hsp90.

<span class="mw-page-title-main">TSC1</span>

Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the TSC1 gene.

<span class="mw-page-title-main">Folliculin</span> Protein-coding gene

The tumor suppressor Folliculin also known as FLCN or Birt-Hogg-Dubé syndrome protein or FLCN_HUMAN, functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt-Hogg-Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.

<span class="mw-page-title-main">Heat shock protein 90kDa alpha (cytosolic), member A1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene.

<span class="mw-page-title-main">HSPA1B</span> Human gene

Human gene HSPA1B is an intron-less gene which encodes for the heat shock protein HSP70-2, a member of the Hsp70 family of proteins. The gene is located in the major histocompatibility complex, on the short arm of chromosome 6, in a cluster with two paralogous genes, HSPA1A and HSPA1L. HSPA1A and HSPA1B produce nearly identical proteins because the few differences in their DNA sequences are almost exclusively synonymous substitutions or in the three prime untranslated region, heat shock 70kDa protein 1A, from HSPA1A, and heat shock 70kDa protein 1B, from HSPA1B. A third, more modified paralog to these genes exists in the same region, HSPA1L, which shares a 90% homology with the other two.

<span class="mw-page-title-main">TSC2</span>

Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the TSC2 gene.

<span class="mw-page-title-main">CDC37</span> Protein-coding gene in the species Homo sapiens

Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene.

<span class="mw-page-title-main">HSP90AB1</span>

Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene.

<span class="mw-page-title-main">PTGES3</span>

Prostaglandin E synthase 3 (cytosolic) is an enzyme that in humans is encoded by the PTGES3 gene.

<span class="mw-page-title-main">Binding immunoglobulin protein</span> Protein-coding gene in the species Homo sapiens

Binding immunoglobulin protein (BiP) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the HSPA5 gene.

<span class="mw-page-title-main">PRKAB1</span> Protein-coding gene in the species Homo sapiens

5'-AMP-activated protein kinase subunit beta-1 is an enzyme that in humans is encoded by the PRKAB1 gene.

<span class="mw-page-title-main">DNAJB1</span> Protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily B member 1 is a protein that in humans is encoded by the DNAJB1 gene.

<span class="mw-page-title-main">BAG2</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 2 is a protein that in humans is encoded by the BAG2 gene.

<span class="mw-page-title-main">AHSA1</span> Protein-coding gene in the species Homo sapiens

Activator of 90 kDa heat shock protein ATPase homolog 1 is an enzyme that in humans is encoded by the AHSA1 gene.

<span class="mw-page-title-main">GHKL domain</span>

The GHKL domain is an evolutionary conserved protein domain.

<span class="mw-page-title-main">Hsp90 inhibitor</span>

An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG).

The chaperone code refers to post-translational modifications of molecular chaperones that control protein folding. Whilst the genetic code specifies how DNA makes proteins, and the histone code regulates histone-DNA interactions, the chaperone code controls how proteins are folded to produce a functional proteome.

<span class="mw-page-title-main">Mehdi Mollapour</span>

Mehdi Mollapour is a British-American Biochemist and Cancer Biologist. He is a Professor, Vice Chair for Translational Research and Director of Renal Cancer Biology Program for the Department of Urology, and Adjunct Professor at the Department of Biochemistry and Molecular Biology at SUNY Upstate Medical University.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000217128 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 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. 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. 1 2 3 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. 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.