CDC37 explained

Symbol:	CDC37_N
Cdc37 N terminal kinase binding
Pfam:	PF03234
Interpro:	IPR013855
Scop:	1us7

Symbol:	CDC37_M
Cdc37 Hsp90 binding domain
Pfam:	PF08565
Interpro:	IPR013874
Scop:	1us7

Symbol:	CDC37_C
Cdc37 C terminal domain
Pfam:	PF08564
Interpro:	IPR013873
Scop:	1us7

Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene.^[1] This protein is highly similar to Cdc 37, a cell division cycle control protein of Saccharomyces cerevisiae. This protein is a HSP90 Co-chaperone^[2] with specific function in cell signal transduction. It has been shown to form complex with Hsp90 and a variety of protein kinases including CDK4, CDK6, SRC, RAF1, MOK, as well as eIF-2 alpha kinases. It is thought to play a critical role in directing Hsp90 to its target kinases.^[3]

Interactions

CDC37 has been shown to interact with:

• CDK4,^{[4] [5] [6]}
• HSP90AA1^{[7] [8]}
• IKBKG,^{[9] [10]}
• IKK2,^[10] and
• STK11.^[11]

Domain architecture

CDC37 consists of three structural domains. The N-terminal domain binds to protein kinases.^[12] The central domain is the Hsp90 chaperone (heat shock protein 90) binding domain.^[13] The function of the C-terminal domain is unclear.

Further reading

• Dey B, Lightbody JJ, Boschelli F . CDC37 is required for p60v-src activity in yeast . Molecular Biology of the Cell . 7 . 9 . 1405–1417 . September 1996 . 8885235 . 275990 . 10.1091/mbc.7.9.1405 .
• Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J . 6 . Interaction between Cdc37 and Cdk4 in human cells . Oncogene . 14 . 16 . 1999–2004 . April 1997 . 9150368 . 10.1038/sj.onc.1201036 . free .
• Kimura Y, Rutherford SL, Miyata Y, Yahara I, Freeman BC, Yue L, Morimoto RI, Lindquist S . 6 . Cdc37 is a molecular chaperone with specific functions in signal transduction . Genes & Development . 11 . 14 . 1775–1785 . July 1997 . 9242486 . 10.1101/gad.11.14.1775 . free .
• Silverstein AM, Grammatikakis N, Cochran BH, Chinkers M, Pratt WB . p50(cdc37) binds directly to the catalytic domain of Raf as well as to a site on hsp90 that is topologically adjacent to the tetratricopeptide repeat binding site . The Journal of Biological Chemistry . 273 . 32 . 20090–20095 . August 1998 . 9685350 . 10.1074/jbc.273.32.20090 . free .
• Grammatikakis N, Lin JH, Grammatikakis A, Tsichlis PN, Cochran BH . p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function . Molecular and Cellular Biology . 19 . 3 . 1661–1672 . March 1999 . 10022854 . 83960 . 10.1128/mcb.19.3.1661 .
• O'Keeffe B, Fong Y, Chen D, Zhou S, Zhou Q . Requirement for a kinase-specific chaperone pathway in the production of a Cdk9/cyclin T1 heterodimer responsible for P-TEFb-mediated tat stimulation of HIV-1 transcription . The Journal of Biological Chemistry . 275 . 1 . 279–287 . January 2000 . 10617616 . 10.1074/jbc.275.1.279 . free .
• Hartson SD, Irwin AD, Shao J, Scroggins BT, Volk L, Huang W, Matts RL . p50(cdc37) is a nonexclusive Hsp90 cohort which participates intimately in Hsp90-mediated folding of immature kinase molecules . Biochemistry . 39 . 25 . 7631–7644 . June 2000 . 10858314 . 10.1021/bi000315r .
• Shao J, Grammatikakis N, Scroggins BT, Uma S, Huang W, Chen JJ, Hartson SD, Matts RL . 6 . Hsp90 regulates p50(cdc37) function during the biogenesis of the activeconformation of the heme-regulated eIF2 alpha kinase . The Journal of Biological Chemistry . 276 . 1 . 206–214 . January 2001 . 11036079 . 10.1074/jbc.M007583200 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–1795 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Rao J, Lee P, Benzeno S, Cardozo C, Albertus J, Robins DM, Caplan AJ . Functional interaction of human Cdc37 with the androgen receptor but not with the glucocorticoid receptor . The Journal of Biological Chemistry . 276 . 8 . 5814–5820 . February 2001 . 11085988 . 10.1074/jbc.M007385200 . free .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–292 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Scholz GM, Cartledge K, Hall NE . Identification and characterization of Harc, a novel Hsp90-associating relative of Cdc37 . The Journal of Biological Chemistry . 276 . 33 . 30971–30979 . August 2001 . 11413142 . 10.1074/jbc.M103889200 . free .
• Chen G, Cao P, Goeddel DV . TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90 . Molecular Cell . 9 . 2 . 401–410 . February 2002 . 11864612 . 10.1016/S1097-2765(02)00450-1 . free .
• Siligardi G, Panaretou B, Meyer P, Singh S, Woolfson DN, Piper PW, Pearl LH, Prodromou C . 6 . Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc37 . The Journal of Biological Chemistry . 277 . 23 . 20151–20159 . June 2002 . 11916974 . 10.1074/jbc.M201287200 . free .
• Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N . Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function . The Journal of Biological Chemistry . 277 . 42 . 39858–39866 . October 2002 . 12176997 . 10.1074/jbc.M206322200 . free .
• Abbas-Terki T, Briand PA, Donzé O, Picard D . The Hsp90 co-chaperones Cdc37 and Sti1 interact physically and genetically . Biological Chemistry . 383 . 9 . 1335–1342 . September 2002 . 12437126 . 10.1515/BC.2002.152 . 9277739 .
• Boudeau J, Deak M, Lawlor MA, Morrice NA, Alessi DR . Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability . The Biochemical Journal . 370 . Pt 3 . 849–857 . March 2003 . 12489981 . 1223241 . 10.1042/BJ20021813 .

Notes and References

1. Dai K, Kobayashi R, Beach D . Physical interaction of mammalian CDC37 with CDK4 . The Journal of Biological Chemistry . 271 . 36 . 22030–22034 . September 1996 . 8703009 . 10.1074/jbc.271.36.22030 . free .
2. Mollapour M, Neckers L . Post-translational modifications of Hsp90 and their contributions to chaperone regulation . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1823 . 3 . 648–655 . March 2012 . 21856339 . 3226900 . 10.1016/j.bbamcr.2011.07.018 .
3. Web site: Entrez Gene: CDC37 cell division cycle 37 homolog (S. cerevisiae).
4. Stepanova L, Leng X, Parker SB, Harper JW . Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 . Genes & Development . 10 . 12 . 1491–1502 . June 1996 . 8666233 . 10.1101/gad.10.12.1491 . free .
5. Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D . 6 . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .
6. Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J . 6 . Interaction between Cdc37 and Cdk4 in human cells . Oncogene . 14 . 16 . 1999–2004 . April 1997 . 9150368 . 10.1038/sj.onc.1201036 . free .
7. Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH . 6 . The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37) . Cell . 116 . 1 . 87–98 . January 2004 . 14718169 . 10.1016/S0092-8674(03)01027-4 . 797232 . free .
8. Silverstein AM, Grammatikakis N, Cochran BH, Chinkers M, Pratt WB . p50(cdc37) binds directly to the catalytic domain of Raf as well as to a site on hsp90 that is topologically adjacent to the tetratricopeptide repeat binding site . The Journal of Biological Chemistry . 273 . 32 . 20090–20095 . August 1998 . 9685350 . 10.1074/jbc.273.32.20090 . free .
9. Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . 6 . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . February 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
10. Chen G, Cao P, Goeddel DV . TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90 . Molecular Cell . 9 . 2 . 401–410 . February 2002 . 11864612 . 10.1016/S1097-2765(02)00450-1 . free .
11. Boudeau J, Deak M, Lawlor MA, Morrice NA, Alessi DR . Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability . The Biochemical Journal . 370 . Pt 3 . 849–857 . March 2003 . 12489981 . 1223241 . 10.1042/BJ20021813 .
12. Kimura Y, Rutherford SL, Miyata Y, Yahara I, Freeman BC, Yue L, Morimoto RI, Lindquist S . 6 . Cdc37 is a molecular chaperone with specific functions in signal transduction . Genes & Development . 11 . 14 . 1775–1785 . July 1997 . 9242486 . 10.1101/gad.11.14.1775 . free .
13. Turnbull EL, Martin IV, Fantes PA . Cdc37 maintains cellular viability in Schizosaccharomyces pombe independently of interactions with heat-shock protein 90 . The FEBS Journal . 272 . 16 . 4129–4140 . August 2005 . 16098195 . 10.1111/j.1742-4658.2005.04825.x . 23442218 . free .