Skip to main content

Advertisement

Log in

An In-Silico Investigation of Key Lysine Residues and Their Selection for Clearing off Aβ and Holo-AβPP Through Ubiquitination

  • Original Research Article
  • Published:
Interdisciplinary Sciences: Computational Life Sciences Aims and scope Submit manuscript

Abstract

Malicious progression of neurodegeneration is a consequence of toxic aggregates of proteins or peptides such as amyloid beta (Aβ) reported in Alzheimer’s disease (AD). These aggregates hinder the electrochemical transmission at neuronal junctions and thus deteriorate neuronal-health by triggering dementia. Electrostatic and hydrophobic interactions among amino-acid residues are the governing principle behind the self-assembly of aforesaid noxious oligomers or agglomerate. Interestingly, lysine residues are crucial for these interactions and for facilitating the clearance of toxic metabolites through the ubiquitination process. The mechanisms behind lysine selectivity and modifications of target proteins are very intriguing process and an avenue to explore the clearance of unwanted proteins from neurons. Therefore, it is fascinating for the researchers to investigate the role of key lysine, their selectivity and interactions with other amino acids to clear-off toxic products in exempting the progression of Neurodegenerative disorders (NDDs). Herein, (1) we identified the aggregation prone sequence in Aβ40 and Aβ42 as ‘HHQKLVFFAE’ and ‘SGYEVHHQKLVFFAEDVG/KGAIIGLMVGGV’ respectively with critical lysine (K) at 16 and 28 for stabilizing the aggregates; (2) elucidated the interaction pattern of AβPP with other Alzheimer’s related proteins BACE1, APOE, SNCA, APBB1, CASP8, NAE1, ADAM10, and PSEN1 to describe the pathophysiology; (3) found APOE as commonly interacting factor between amyloid beta and Tau for governing AD pathogenesis; (4) reported K224, K351, K363, K377, K601, K662, K751, and K763 as potential putative lysine for facilitating AβPP clearance through ubiquitination thereby arresting Aβ formation; and (5) observed conserved glutamine (Q), glutamic acid (E), and alpha-helical conformation as few crucial factors for lysine selectivity in the ubiquitination of AβPP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Alzheimer’s Association (2017) Alzheimer’s disease facts and figures. Alzheimers Dement 13:325–373

    Article  Google Scholar 

  2. Armstrong RA (2009) The molecular biology of senile plaques and neurofibrillary tangles in Alzheimer’s disease. 47(4):289–299

  3. Bohm C, Chen F, Sevalle J, Qamar S, Dodd R, Li Y, Schmitt-Ulms G, Fraser PE, St George-Hyslop PH (2015) Current and future implications of basic and translational research on amyloid-β peptide production and removal pathways. Mol Cell Neurosci 66:3–11. https://doi.org/10.1016/j.mcn.2015.02.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mo P, Wang H, Lu H, Boyd DD, Yan C (2010) MDM2 mediates ubiquitination and degradation of activating transcription factor 3. J Biol Chem 285(35):26908–26915. https://doi.org/10.1074/jbc.M110.132597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nomura J, Hosoi T, Kaneko M, Ozawa K, Nishi A, Nomura Y (2016) Neuroprotection by endoplasmic reticulum stress-induced HRD1 and chaperones: possible therapeutic targets for Alzheimer’s and Parkinson’s disease. Med Sci 4:14

    Google Scholar 

  6. Stankowski JN, Zeiger SLH, Cohen EL, DeFranco DB, Cai J, McLaughlin B (2011) C-terminus of heat shock cognate 70 interacting protein increases following stroke and impairs survival against acute oxidative stress. Antioxid Redox Signal 14(10):1787–1801. https://doi.org/10.1089/ars.2010.3300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cleveland DW, Yamanaka K, Bomont P (2009) Gigaxonin controls vimentin organization through a tubulin chaperone-independent pathway. Hum Mol Genet 18(8):1384–1394. https://doi.org/10.1093/hmg/ddp044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen Y, Neve RL, Liu H (2012) Neddylation dysfunction in Alzheimer’s disease. J Cell Mol Med 16(11):2583–2591. https://doi.org/10.1111/j.1582-4934.2012.01604.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. David Y, Ternette N, Edelmann MJ, Ziv T, Gayer B, Sertchook R, Dadon Y, Kessler BM, Navon A (2011) E3 ligases determine ubiquitination site and conjugate type by enforcing specificity on E2 enzymes. J Biol Chem 286(51):44104–44115. https://doi.org/10.1074/jbc.M111.234559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Morris JR, Solomon E (2004) BRCA1: BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum Mol Genet 13(8):807–817

    Article  CAS  PubMed  Google Scholar 

  11. Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132(3):344–362. https://doi.org/10.1016/j.cell.2008.01.020

    Article  CAS  PubMed  Google Scholar 

  12. Al-Hakim AK, Zagorska A, Chapman L, Deak M, Peggie M, Alessi DR (2008) Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains. Biochem J 411(2):249–260. https://doi.org/10.1042/BJ20080067

    Article  CAS  PubMed  Google Scholar 

  13. Bergink S, Jentsch S (2009) Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458:461–467

    Article  CAS  PubMed  Google Scholar 

  14. Matsumoto ML, Wickliffe KE, Dong KC, Yu C, Bosanac I, Bustos D, Phu L, Kirkpatrick DS, Hymowitz SG, Rape M, Kelley RF, Dixit VM (2010) K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody. Mol Cell 39(3):477–484. https://doi.org/10.1016/j.molcel.2010.07.001

    Article  CAS  PubMed  Google Scholar 

  15. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Touw WG, Baakman C, Black J, te Beek TAH, Krieger E, Joosten RP, Vriend G (2015) A series of PDB-related databanks for everyday needs. Nucleic Acids Res 43(Database issue):D364–D368. https://doi.org/10.1093/nar/gku1028

    Article  CAS  PubMed  Google Scholar 

  17. Rose AS, Hildebrand PW (2015) NGL viewer: a web application for molecular visualization. Nucleic Acids Res 43(Web Server issue):W576–W579. https://doi.org/10.1093/nar/gkv402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C (2015) STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43(Database issue):D447–D452. https://doi.org/10.1093/nar/gku1003

    Article  CAS  PubMed  Google Scholar 

  19. Radivojac P, Vacic V, Haynes C, Cocklin RR, Mohan A, Heyen JW, Goebl MG, Iakoucheva LM (2010) Identification, analysis and prediction of protein ubiquitination sites. Proteins Struct Funct Bioinform 78(2):365–380

    Article  CAS  Google Scholar 

  20. Tung CW, Ho SY (2008) Computational identification of ubiquitylation sites from protein sequences. BMC Bioinform 9:310. https://doi.org/10.1186/1471-2105-9-310

    Article  CAS  Google Scholar 

  21. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22(22):4673–4680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hall T (2011) BioEdit: an important software for molecular biology. GERF Bull Biosci 2(1):60–61

    Google Scholar 

  23. Buchan DWA, Minneci F, Nugent TCO, Bryson K, Jones DT (2013) Scalable web services for the PSIPRED Protein Analysis Workbench. Nucleic Acids Res 41(W1):W340–W348

    Article  Google Scholar 

  24. Sinha S, Lopes DH, Bitan G (2012) A key role for lysine residues in amyloid β-protein folding, assembly, and toxicity. ACS Chem Neurosci 3(6):473–481. https://doi.org/10.1021/cn3000247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, Tycko R (2002) A structural model for Alzheimer’s β-amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci USA 99:16742–16747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Petkova AT, Yau WM, Tycko R (2006) Experimental constraints on quaternary structure in Alzheimer’s β-amyloid fibrils. Biochemistry 45:498–512

    Article  CAS  PubMed  Google Scholar 

  27. Selkoe DJ, Podlisny MB (2002) Deciphering the genetic basis of Alzheimer’s disease. Annu Rev Genom Hum Genet 3:67–99

    Article  CAS  Google Scholar 

  28. Chang YJ, Chen YR (2014) The coexistence of an equal amount of Alzheimer’s amyloid-β 40 and 42 forms structurally stable and toxic oligomers through a distinct pathway. FEBS J 281(11):2674–2687. https://doi.org/10.1111/febs.12813

    Article  CAS  PubMed  Google Scholar 

  29. Vandersteen A, Hubin E, Sarroukh R, De Baets G, Schymkowitz J, Rousseau F, Subramaniam V, Raussens V, Wenschuh H, Wildemann D, Broersen K (2012) A comparative analysis of the aggregation behavior of amyloid-β peptide variants. FEBS Lett 586(23):4088–4093. https://doi.org/10.1016/j.febslet.2012.10.022

    Article  CAS  PubMed  Google Scholar 

  30. Perreau VM, Orchard S, Adlard PA, Bellingham SA, Cappai R, Ciccotosto GD, Cowie TF, Crouch PJ, Duce JA, Evin G, Faux NG, Hill AF, Hung YH, James SA, Li QX, Mok SS, Tew DJ, White AR, Bush AI, Hermjakob H, Masters CL (2010) A domain level interaction network of amyloid precursor protein and Abeta of Alzheimer’s disease. Proteomics 10(12):2377–2395. https://doi.org/10.1002/pmic.200900773

    Article  CAS  PubMed  Google Scholar 

  31. Lopes D, Sinha S, Bitan G (2011) A key role for lysine residues in amyloid-β protein folding, assembly, and toxicity. Alzheimer’s Dement 7(4):S465–S466. https://doi.org/10.1016/j.jalz.2011.05.1349

    Article  Google Scholar 

  32. Bera S, Korshavn KJ, Kar RK, Lim MH, Ramamoorthy A, Bhunia A (2016) Biophysical insights into the membrane interaction of the core amyloid-forming Aβ40 fragment K16-K28 and its role in the pathogenesis of Alzheimer’s disease. Phys Chem Chem Phys 18(25):16890–16901. https://doi.org/10.1039/c6cp02023b

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thanks the senior management of Delhi Technological University for constant support and encouragement.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pravir Kumar.

Ethics declarations

Conflict of interest

There is no conflict or competing interest declared by the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, D., Kumar, P. An In-Silico Investigation of Key Lysine Residues and Their Selection for Clearing off Aβ and Holo-AβPP Through Ubiquitination. Interdiscip Sci Comput Life Sci 11, 584–596 (2019). https://doi.org/10.1007/s12539-018-0307-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12539-018-0307-2

Keywords

Navigation