Şaperon BIP’nin iki durumlu anahtarı: Kanser ve nörodejenerasyonda endoplazmik retikulum stresi için ilaçlanabilir bir hedef
Abstract
Amaç: Endoplazmik retikulum (ER) şaperonu BiP, katlanmamış protein yanıtının merkezi bir düğümüdür ve ER stresinin tetiklediği kanser ve nörodejenerasyon gibi hastalıklarda kilit bir terapötik hedeftir. Ancak, substrat bağlama ve salıverme döngüsünü yöneten konformasyonel dinamiklerin tam olarak anlaşılamaması, terapötik geliştirmeyi güçleştirmektedir.
Gereç ve Yöntem: İnsan BiP’sinin (PDB: 5e84) substrat bağlama domaini alfa (SBDα) esnekliğini karakterize etmek için 100 nanosaniyelik tüm-atom moleküler dinamik simülasyonu gerçekleştirdik. Konformasyonel durumları haritalamak için RMSD, domainler arası mesafeler ve serbest enerji yüzeyini analiz ettik.
Bulgular: Simülasyonlarımız, BiP’nin iki ayrı, düşük enerjili konformasyonel durumda var olduğunu ortaya koydu: baskın “uzamış” durum (%90 doluluk oranı) ve geçici “bükülmüş” durum. SBDα, ~10 ns zaman ölçeğinde, kilit domainler arasındaki mesafelerin ~25 Å’dan ~3 Å’a çöktüğü hızlı bir bükülme--geri-dönüş hareketi sergiler. Bu hareket, 25–30 kJ/mol düzeyinde orta şiddette bir enerji bariyerine sahip moleküler bir anahtarı temsil eder ve fizyolojik sıcaklıklarda erişilebilir kılar.
Sonuç: Tanımlanan iki-durumlu konformasyonel anahtar, BiP’in dinamik substrat yönetimini açıklayan işlevsel açıdan kritik bir özelliktir ve “ilaçlanabilir” bir mekanizma sunar. Uzamış veya bükülmüş durumun küçük moleküllerle stabilize edilmesi, BiP aktivitesinin modülasyonu için somut bir terapötik strateji sağlar; örneğin kanserdeki hayatta kalma yanlısı işlevin inhibisyonu ya da nörodejenerasyondaki koruyucu rolün güçlendirilmesi gibi.
Keywords
HSPA5 proteini Endoplazmik Retikulum Stresi Moleküler Dinamik Simülasyonu Protein Konformasyonu Neoplazmlar
References
- Fernández L, Kong CS, Alkhoury M, Tryfonos M, Brighton PJ, et al. The endoplasmic reticulum protein HSPA5/BiP is essential for decidual transformation of human endometrial stromal cells. Sci Rep. 2024;14(1).
- Li T, Fu J, Cheng J, Elfiky AA, Wei C, et al. New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19. Front Immunol. 2023;14:1166680.
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The two-state switch of chaperone BIP: A druggable target for endoplasmic reticulum stress in cancer and neurodegeneration
Abstract
Aim: The endoplasmic reticulum (ER) chaperone BiP is a central node in the unfolded protein response and a key therapeutic target in diseases driven by ER stress, such as cancer and neurodegeneration. However, therapeutic development is hampered by an incomplete understanding of the conformational dynamics that govern its substrate binding and release cycle.
Materials and Methods: We performed a 100-nanosecond all-atomic molecular dynamics simulation of human BiP (PDB: 5e84) to characterize the flexibility of its substrate binding domain alpha (SBDα). We analyzed RMSD, inter-domain distances, and the free energy landscape to map its conformational states.
Results: Our simulations revealed that BiP exists in two distinct, low-energy conformational states: a predominant "extended" state (90% occupancy) and a transient "bent" state. The SBDα undergoes a rapid bending-restoring motion, with distances between key domains collapsing from ~25 Å to 3 Å within a 10 ns timescale. This motion represents a molecular switch with a moderate energy barrier of 25-30 kJ/mol, making it accessible at physiological temperatures.
Conclusions: The identified two-state conformational switch is a functionally critical feature that explains BiP's dynamic substrate handling. This molecular motion represents a "druggable" mechanism. Stabilizing either the extended or bent state with small molecules offers a tangible therapeutic strategy for modulating BiP activity, such as inhibiting its pro-survival function in cancer or enhancing its protective role in neurodegeneration.
Keywords
HSPA5 protein Endoplasmic Reticulum Stress Molecular Dynamics Simulation Protein Conformation Neoplasms
Ethical Statement
This study did not involve human subjects, animal experiments, or other ethical considerations requiring institutional review board approval.
Thanks
This study was derived from the PhD thesis of Zekeriya Düzgün. The numerical calculations reported in this paper were partially performed at TUBITAK ULAKBIM, High Performance, and Grid Computing Center (TRUBA resources). Declaration of generative AI and AI-assisted technologies: During the preparation of this work, the author(s) used Anthropic Claude 4.0 and Google Gemini 2.5 pro in order to assist with language editing, grammar correction, manuscript formatting. After using these tools/services, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.
References
- Fernández L, Kong CS, Alkhoury M, Tryfonos M, Brighton PJ, et al. The endoplasmic reticulum protein HSPA5/BiP is essential for decidual transformation of human endometrial stromal cells. Sci Rep. 2024;14(1).
- Li T, Fu J, Cheng J, Elfiky AA, Wei C, et al. New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19. Front Immunol. 2023;14:1166680.
- Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):352.
- Obaseki I, Ndolo CC, Adedeji AA, Popoola HO, Kravats AN. The structural and functional dynamics of BiP and Grp94: opportunities for therapeutic discovery. Trends Pharmacol Sci. 2025;46(5):453–67.
- Hendershot LM, Buck TM, Brodsky JL. The Essential Functions of Molecular Chaperones and Folding Enzymes in Maintaining Endoplasmic Reticulum Homeostasis. J Mol Biol. 2024;436(14).
- Yang J, Nune M, Zong Y, Zhou L, Liu Q. Close and Allosteric Opening of the Polypeptide-Binding Site in a Human Hsp70 Chaperone BiP. Structure. 2015;23(12):2191–203.
- Brown BP, Stein RA, Meiler J, Mchaourab HS. Approximating Projections of Conformational Boltzmann Distributions with AlphaFold2 Predictions: Opportunities and Limitations. J Chem Theory Comput. 2024;20(3):1434–47.
- Meersche Y Vander, Cretin G, Gheeraert A, Gelly JC, Galochkina T. ATLAS: protein flexibility description from atomistic molecular dynamics simulations. Nucleic Acids Res. 2024;52(D1):D384–92.
- Dunbrack RL, Karplus M. Backbone-dependent Rotamer Library for Proteins Application to Side-chain Prediction. J Mol Biol. 1993;230(2):543–74.
- Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, et al. UCSF Chimera - A visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605–12.
- Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1–2:19–25.
- Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, et al. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins Struct Funct Bioinforma. 2010;78(8):1950–8.
- Bussi G, Donadio D, Parrinello M. Canonical sampling through velocity rescaling. J Chem Phys. 2007;126(1):014101.
- Berendsen HJCC, Postma JPMM van, Van Gunsteren WF, Dinola A, Haak JR. Molecular dynamics with coupling to an external bath. J Chem Phys. 1984;81(8):3684–90.
- Nosé S. A molecular dynamics method for simulations in the canonical ensemble. Mol Phys. 1984;52(2):255–68.
- Parrinello M, Rahman A. Polymorphic transitions in single crystals: A new molecular dynamics method. J Appl Phys. 1981;52(12):7182–90.
- Darden T, York D, Pedersen L. Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems. J Chem Phys. 1993;98(12):10089–92.
- Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, et al. A smooth particle mesh Ewald method. J Chem Phys. 1995;103(19):8577–93.
- Hess B, Bekker H, Berendsen HJCC, Fraaije JGEMEM. LINCS: A linear constraint solver for molecular simulations. J Comput Chem. 1997;18(12):1463–72.
- Bakan A, Meireles LM, Bahar I. ProDy: Protein Dynamics Inferred from Theory and Experiments. Bioinformatics. 2011;27(11):1575–7.
- Humphrey W, Dalke A, Schulten K. VMD: Visual molecular dynamics. J Mol Graph. 1996;14(1):33–8.
- Kumari R, Kumar R, Lynn A. G-mmpbsa -A GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model. 2014;54(7):1951–62.
- Bard JAM, Drummond DA. Chaperone regulation of biomolecular condensates. Front Biophys. 2024;2:1342506.
- Preissler S, Rohland L, Yan Y, Chen R, Read RJ, et al. AMPylation targets the rate-limiting step of BiP’s ATPase cycle for its functional inactivation. Elife. 2017;6.
- Dawes S, Hurst N, Grey G, Wieteska L, Wright N V., et al. Chaperone BiP controls ER stress sensor Ire1 through interactions with its oligomers. Life Sci Alliance. 2024;7(10):e202402702.
Details
| Primary Language | English |
|---|---|
| Subjects | Medical Molecular Engineering of Nucleic Acids and Proteins |
| Journal Section | Research Article |
| Authors | |
| Submission Date | July 24, 2025 |
| Acceptance Date | September 12, 2025 |
| Publication Date | March 9, 2026 |
| DOI | https://doi.org/10.19161/etd.1750148 |
| IZ | https://izlik.org/JA38TP77TZ |
| Published in Issue | Year 2026 Volume: 65 Issue: 1 |
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