The two-state switch of chaperone BIP: A druggable target for endoplasmic reticulum stress in cancer and neurodegeneration

Zekeriya Düzgün; Zuhal Eroğlu

doi:10.19161/etd.1750148

TR EN

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

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

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.

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Details

Primary Language

English

Subjects

Medical Molecular Engineering of Nucleic Acids and Proteins

Journal Section

Research Article

Authors

Zekeriya Düzgün ^*
0000-0001-6420-6292
Türkiye

Zuhal Eroğlu
0000-0003-1720-8206
Türkiye

Publication Date

March 9, 2026

Submission Date

July 24, 2025

Acceptance Date

September 12, 2025

Published in Issue

Year 2026 Volume: 65 Number: 1

DOI

https://doi.org/10.19161/etd.1750148

IZ

https://izlik.org/JA38TP77TZ

Cite

RIS / Bibtex

APA

Düzgün, Z., & Eroğlu, Z. (2026). The two-state switch of chaperone BIP: A druggable target for endoplasmic reticulum stress in cancer and neurodegeneration. Ege Tıp Dergisi, 65(1), 11-17. https://doi.org/10.19161/etd.1750148

AMA

1.Düzgün Z, Eroğlu Z. The two-state switch of chaperone BIP: A druggable target for endoplasmic reticulum stress in cancer and neurodegeneration. EJM. 2026;65(1):11-17. doi:10.19161/etd.1750148

Chicago

Düzgün, Zekeriya, and Zuhal Eroğlu. 2026. “The Two-State Switch of Chaperone BIP: A Druggable Target for Endoplasmic Reticulum Stress in Cancer and Neurodegeneration”. Ege Tıp Dergisi 65 (1): 11-17. https://doi.org/10.19161/etd.1750148.

EndNote

Düzgün Z, Eroğlu Z (March 1, 2026) The two-state switch of chaperone BIP: A druggable target for endoplasmic reticulum stress in cancer and neurodegeneration. Ege Tıp Dergisi 65 1 11–17.

IEEE

[1]Z. Düzgün and Z. Eroğlu, “The two-state switch of chaperone BIP: A druggable target for endoplasmic reticulum stress in cancer and neurodegeneration”, EJM, vol. 65, no. 1, pp. 11–17, Mar. 2026, doi: 10.19161/etd.1750148.

ISNAD

Düzgün, Zekeriya - Eroğlu, Zuhal. “The Two-State Switch of Chaperone BIP: A Druggable Target for Endoplasmic Reticulum Stress in Cancer and Neurodegeneration”. Ege Tıp Dergisi 65/1 (March 1, 2026): 11-17. https://doi.org/10.19161/etd.1750148.

JAMA

1.Düzgün Z, Eroğlu Z. The two-state switch of chaperone BIP: A druggable target for endoplasmic reticulum stress in cancer and neurodegeneration. EJM. 2026;65:11–17.

MLA

Düzgün, Zekeriya, and Zuhal Eroğlu. “The Two-State Switch of Chaperone BIP: A Druggable Target for Endoplasmic Reticulum Stress in Cancer and Neurodegeneration”. Ege Tıp Dergisi, vol. 65, no. 1, Mar. 2026, pp. 11-17, doi:10.19161/etd.1750148.

Vancouver

1.Zekeriya Düzgün, Zuhal Eroğlu. The two-state switch of chaperone BIP: A druggable target for endoplasmic reticulum stress in cancer and neurodegeneration. EJM. 2026 Mar. 1;65(1):11-7. doi:10.19161/etd.1750148