NAE1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNAE1, A-116A10.1, APPBP1, ula-1, HPP1, NEDD8 activating enzyme E1 subunit 1
External IDsOMIM: 603385 MGI: 2384561 HomoloGene: 68370 GeneCards: NAE1
Orthologs
SpeciesHumanMouse
Entrez

8883

234664

Ensembl

ENSG00000159593

ENSMUSG00000031878

UniProt

Q13564

Q8VBW6

RefSeq (mRNA)

NM_001018159
NM_001018160
NM_001286500
NM_003905

NM_144931

RefSeq (protein)

NP_001018169
NP_001018170
NP_001273429
NP_003896

NP_659180

Location (UCSC)Chr 16: 66.8 – 66.87 MbChr 8: 105.24 – 105.26 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene.[5][6][7]

Function

The protein encoded by this gene binds to the beta-amyloid precursor protein. Beta-amyloid precursor protein is a cell surface protein with signal-transducing properties, and it is thought to play a role in the pathogenesis of Alzheimer's disease. In addition, the encoded protein can form a heterodimer with UBE1C and bind and activate NEDD8, a ubiquitin-like protein. This protein is required for cell cycle progression through the S/M checkpoint. Three transcript variants encoding different isoforms have been found for this gene.[7]

APPBP1 (Amyloid Precursor Protein-Binding Protein 1) binds to the Amyloid Precursor Protein (APP) carboxy terminal domain.[8] APPBP1 is a multi-functional protein with activities in neuronal tissues. APPBP1 also bonds with UBA3 (ubiquitin-like protein-activating enzyme 3[9]) to form the NEDD8 activating enzyme (NAE). Activated NEDD8 is an enzyme that regulates multiple cellular pathways.

History

APPBP1 was first cloned and identified by its interaction with the C-terminus of beta-amyloid protein precursor (precursor to beta-amyloid present in Alzheimer's disease) in 1996.[5] APPBP1 was first studied for its potential neuronal effects, and neuronal effects continue to be further investigated (e.g. references[10][11]).

Role in NEDD8 activation

APPBP1 can bind to UBA3 to form the NEDD8 activating enzyme (NAE) (homologous to the ubiquitin-activating enzymes, also known as E1 enzymes). When NEDD8 is activated it can neddylate (and thereby alter the activity of) target proteins. Neddylation has emerged as a major regulatory pathway with a critical role, among others, in cell cycle progression and survival. Proteins that are neddylated include the DNA replication licensing factor Cdt-1, the NF-κB transcription factor inhibitor pIκBα, and the cell cycle regulators cyclin E and p27.[12] Thus, APPBP1 carries out an initiating step that controls major regulatory pathways in the cell.

The first step in activation of NEDD8 by NAE is the extensive interaction of the acidic face of NEDD8’s globular domain with the catalytic cysteine domain portion of the APPBP1 component of NAE.[13] The interface between NEDD8 and APPBP1 involves the helix and subsequent loop in NEDD8 and a sub-domain comprising APPBP1’s residues 178–280 that serves as a wall for the broad, deep groove in the APPBP1-UBA3 structure. The nature of this interface is predominantly polar, with 11 residues from NEDD8 forming a network of hydrogen bonds and salt bridges with 9 residues from the APPBP1 component of NAE.

Subsequent activation steps were described by Walden et al.,[13] and Schulman.[14] NEDD8 interacts with an adenylation pocket of the UBA3 part of the heterodimeric NAE to form covalently linked NEDD8-AMP. NEDD8 then forms a covalent thioester bond with a reactive cysteine of the UBA3 part of NAE. After this, a second NEDD8 is attracted to APPBP1 followed by adenylation in the UBA3 adenylation pocket. The activated NAE is thus loaded with two NEDD8 molecules asymmetrically arranged.

Role in DNA repair

After activation of NEDD8, initiated by APPBP1, NEDD8 interaction at DNA-damage sites is a highly dynamic process.[15] Neddylation is needed during a short period of the global genome repair (GGR) sub-pathway of DNA nucleotide excision repair (NER). When DNA damage is produced by UV irradiation, CUL4A in the DNA damage binding protein 2 (DDB2) complex is activated by NEDD8, and this activated complex allows GGR-NER to proceed to remove the damage.[16]

Neddylation also has a role in repair of double-strand breaks.[15] Non-homologous end joining(NHEJ) is a DNA repair pathway frequently used to repair DNA double-strand breaks. The first step in this pathway depends on the Ku70/Ku80 heterodimer that forms a highly stable ring structure encircling DNA ends.[17] But the Ku heterodimer needs to be removed when NHEJ is completed, or it can block transcription or replication. The Ku heterodimer is ubiquitylated in a DNA-damage and neddylation-dependent manner to promote the release of Ku and other NHEJ factors from the site of repair after the process is completed.[15]

Role in cancer therapy

When APPBP1 complexes with UBA3 to form the NEDD8 activating enzyme (NAE), it changes the conformation of UBA3 from the free form to a form that can carry out the cascade of actions needed to activate NEDD8.[13] The adenylation pocket of UBA3 in the hetero-dimeric NAE enzyme is critical for NEDD8 activation.

Pevonedistat (MLN4924) is an analog of adenosine sulfamate.[18]

Pevonedistat is a mechanism-based inhibitor of NAE. NAE catalyzes formation of a covalent NEDD8-Pevonedistat adduct. The covalent NEDD8-Pevonedistat adduct occupies the same sites as ATP and NEDD8 bound in the adenylation active site in the NAE structure.[18] The NEDD8-Pevonedistat adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-Pevonedistat adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by Pevonedistat.

As described above, activated NEDD8 is needed for at least two pathways of DNA repair, nucleotide excision repair (NER) and non-homologous end joining (NHEJ) (see NEDD8).

One or more DNA repair genes in seven DNA repair pathways are frequently epigenetically silenced in cancers (see e.g. DNA repair pathways).[19]) This is a likely source of the genome instability of cancers. If activation of NEDD8 is inhibited by Pevonedistat, cancer cells will then have an additional induced deficiency of NER or NHEJ. Such cells may then die because of deficient DNA repair leading to accumulation of DNA damages. The effect of NEDD8 inhibition may be greater for cancer cells than for normal cells if the cancer cells are already deficient in DNA repair due to prior epigenetic silencing of DNA repair genes active in alternative pathways (see synthetic lethality).

Clinical trials

In a phase 1 trial of Pevonedistat to determine dosing in patients with AML and myelodysplastic syndromes "modest clinical activity was observed".[20]

More recently, in 2016, Pevonedistat has shown a significant therapeutic effect in three further Phase I clinical cancer trials. These include Pevonedistat trials against relapsed/refractory multiple myeloma or lymphoma,[21] metastatic melanoma,[22] and advanced solid tumors.[23]

Interactions

APPBP1 has been shown to interact with UBE1C,[24] TRIP12[25] and Amyloid precursor protein.[5]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000159593 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031878 - 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 Chow N, Korenberg JR, Chen XN, Neve RL (May 1996). "APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein". The Journal of Biological Chemistry. 271 (19): 11339–46. doi:10.1074/jbc.271.19.11339. PMID 8626687.
  6. ↑ Bohnsack RN, Haas AL (July 2003). "Conservation in the mechanism of Nedd8 activation by the human AppBp1-Uba3 heterodimer". The Journal of Biological Chemistry. 278 (29): 26823–30. doi:10.1074/jbc.M303177200. PMID 12740388.
  7. 1 2 "Entrez Gene: APPBP1 amyloid beta precursor protein binding protein 1".
  8. ↑ Chen Y, McPhie DL, Hirschberg J, Neve RL (March 2000). "The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons". The Journal of Biological Chemistry. 275 (12): 8929–35. doi:10.1074/jbc.275.12.8929. PMID 10722740.
  9. ↑ Liakopoulos D, Doenges G, Matuschewski K, Jentsch S (April 1998). "A novel protein modification pathway related to the ubiquitin system". The EMBO Journal. 17 (8): 2208–14. doi:10.1093/emboj/17.8.2208. PMC 1170565. PMID 9545234.
  10. ↑ Hong BH, Ha S, Joo Y, Kim JA, Chang KA, Woo RS, Suh YH, Kim JH, Kim HS (January 2012). "Amyloid precursor protein binding protein-1 knockdown reduces neuronal differentiation in fetal neural stem cells". NeuroReport. 23 (2): 61–6. doi:10.1097/WNR.0b013e32834e7d4f. PMID 22182960. S2CID 5489608.
  11. ↑ Chen Y, Neve RL, Liu H (November 2012). "Neddylation dysfunction in Alzheimer's disease". Journal of Cellular and Molecular Medicine. 16 (11): 2583–91. doi:10.1111/j.1582-4934.2012.01604.x. PMC 3484225. PMID 22805479.
  12. ↑ Soucy TA, Dick LR, Smith PG, Milhollen MA, Brownell JE (July 2010). "The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy". Genes & Cancer. 1 (7): 708–16. doi:10.1177/1947601910382898. PMC 3092238. PMID 21779466.
  13. 1 2 3 Walden H, Podgorski MS, Huang DT, Miller DW, Howard RJ, Minor DL, Holton JM, Schulman BA (December 2003). "The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1". Molecular Cell. 12 (6): 1427–37. doi:10.1016/s1097-2765(03)00452-0. PMID 14690597.
  14. ↑ Schulman BA (December 2011). "Twists and turns in ubiquitin-like protein conjugation cascades". Protein Science. 20 (12): 1941–54. doi:10.1002/pro.750. PMC 3302639. PMID 22012881.
  15. 1 2 3 Brown JS, Lukashchuk N, Sczaniecka-Clift M, Britton S, le Sage C, Calsou P, Beli P, Galanty Y, Jackson SP (May 2015). "Neddylation promotes ubiquitylation and release of Ku from DNA-damage sites". Cell Reports. 11 (5): 704–14. doi:10.1016/j.celrep.2015.03.058. PMC 4431666. PMID 25921528.
  16. ↑ Groisman R, Polanowska J, Kuraoka I, Sawada J, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y (May 2003). "The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage". Cell. 113 (3): 357–67. doi:10.1016/s0092-8674(03)00316-7. PMID 12732143. S2CID 11639677.
  17. ↑ Walker JR, Corpina RA, Goldberg J (August 2001). "Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair". Nature. 412 (6847): 607–14. doi:10.1038/35088000. PMID 11493912. S2CID 4371575.
  18. 1 2 Brownell JE, Sintchak MD, Gavin JM, Liao H, Bruzzese FJ, Bump NJ, Soucy TA, Milhollen MA, Yang X, Burkhardt AL, Ma J, Loke HK, Lingaraj T, Wu D, Hamman KB, Spelman JJ, Cullis CA, Langston SP, Vyskocil S, Sells TB, Mallender WD, Visiers I, Li P, Claiborne CF, Rolfe M, Bolen JB, Dick LR (January 2010). "Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ". Molecular Cell. 37 (1): 102–11. doi:10.1016/j.molcel.2009.12.024. PMID 20129059.
  19. ↑ Jin B, Robertson KD (2013). "DNA Methyltransferases, DNA Damage Repair, and Cancer". Epigenetic Alterations in Oncogenesis. Advances in Experimental Medicine and Biology. Vol. 754. pp. 3–29. doi:10.1007/978-1-4419-9967-2_1. ISBN 978-1-4419-9966-5. PMC 3707278. PMID 22956494.
  20. ↑ Swords RT, Erba HP, DeAngelo DJ, Bixby DL, Altman JK, Maris M, Hua Z, Blakemore SJ, Faessel H, Sedarati F, Dezube BJ, Giles FJ, Medeiros BC (May 2015). "Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study" (PDF). British Journal of Haematology. 169 (4): 534–43. doi:10.1111/bjh.13323. PMID 25733005. S2CID 46173371.
  21. ↑ Shah JJ, Jakubowiak AJ, O'Connor OA, Orlowski RZ, Harvey RD, Smith MR, Lebovic D, Diefenbach C, Kelly K, Hua Z, Berger AJ, Mulligan G, Faessel HM, Tirrell S, Dezube BJ, Lonial S (January 2016). "Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma". Clinical Cancer Research. 22 (1): 34–43. doi:10.1158/1078-0432.CCR-15-1237. PMC 5694347. PMID 26561559.
  22. ↑ Bhatia S, Pavlick AC, Boasberg P, Thompson JA, Mulligan G, Pickard MD, Faessel H, Dezube BJ, Hamid O (August 2016). "A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma". Investigational New Drugs. 34 (4): 439–49. doi:10.1007/s10637-016-0348-5. PMC 4919369. PMID 27056178.
  23. ↑ Sarantopoulos J, Shapiro GI, Cohen RB, Clark JW, Kauh JS, Weiss GJ, Cleary JM, Mahalingam D, Pickard MD, Faessel HM, Berger AJ, Burke K, Mulligan G, Dezube BJ, Harvey RD (February 2016). "Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors". Clinical Cancer Research. 22 (4): 847–57. doi:10.1158/1078-0432.CCR-15-1338. PMID 26423795.
  24. ↑ Chen Y, McPhie DL, Hirschberg J, Neve RL (March 2000). "The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons". The Journal of Biological Chemistry. 275 (12): 8929–35. doi:10.1074/jbc.275.12.8929. PMID 10722740.
  25. ↑ Park Y, Yoon SK, Yoon JB (September 2008). "TRIP12 functions as an E3 ubiquitin ligase of APP-BP1". Biochemical and Biophysical Research Communications. 374 (2): 294–8. doi:10.1016/j.bbrc.2008.07.019. PMID 18627766.

Further reading

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