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 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]
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]
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]
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.
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.
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.
Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the TSC1 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.
Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 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.
Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the TSC2 gene.
Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene.
Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene.
Prostaglandin E synthase 3 (cytosolic) is an enzyme that in humans is encoded by the PTGES3 gene.
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.
5'-AMP-activated protein kinase subunit beta-1 is an enzyme that in humans is encoded by the PRKAB1 gene.
DnaJ homolog subfamily B member 1 is a protein that in humans is encoded by the DNAJB1 gene.
BAG family molecular chaperone regulator 2 is a protein that in humans is encoded by the BAG2 gene.
Activator of 90 kDa heat shock protein ATPase homolog 1 is an enzyme that in humans is encoded by the AHSA1 gene.
The GHKL domain is an evolutionary conserved protein domain.
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.
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.
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