HnRNPA2’in LC(286-291) Domain Fibrili ve Onun D290V Mutasyonu Hakkında Teorik Bir Çalışma

Year 2021, Volume: 11 Issue: 2, 1080 - 1089, 01.06.2021

Hakan Alıcı

https://doi.org/10.21597/jist.845090

Abstract

Son zamanlarda, hnRNPA'lerin işlevindeki bozukluklar başta amiyotrofik lateral skleroz (ALS) ve frontotemporal demans (FTD) olmak üzere birçok nörodejeneratif hastalıklar ile ilişkilendirilmektedir. hnRNPA'lerin düşük karmaşıklık (LC) domainlerinin fibrilleşme eğilimlerinin bu işlev bozukluklarının temel nedeni olduğu düşünülmektedir. Bu çalışmada atomik yapısı çok yakın zamanda ortaya konulmuş D290V mutasyonuna sahip hnRNPA2'nin LC(286-291) fibril domaininin bir polimorfu (pdb kod:6WPQ) ve bu poliformun mutasyonsuz yani vahşi tip (WT) fibril formu hakkında bir moleküler Dinamik (MD) simülasyon çalışması sunuyoruz. MD simulasyon sonuçlarına göre önerilen fibril polimorf yapısı için D290V mutasyonun kararlı bir konformasyona sahip olduğu ancak onun WT formun bu fibril polimorf yapı konformasyonu için kararsız olduğu tespit edilmiştir. Sonuç olarak çalışmada elde edilen bulgular gelecekteki muhtemel ilaç çalışmaları için yalnızca D290V fibril yapısının hedef yapı olarak ele alınabileceğini işaret etmektedir.

Keywords

Düşük karmaşıklık alanı, moleküler dinamik, simülasyon, D290V

Supporting Institution

Zonguldak Bülent Ecevit Üniversitesi

Project Number

2015-22794455-03

Thanks

Bu çalışmaya 2015-22794455-03 nolu Altyapı Projesi ile maddi kaynak sağlayan Zonguldak Bülent Ecevit Üniversitesi Bilimsel Araştırmalar Proje Birimi’ne teşekkür ederiz.

A Theorotical Study bout LC(286-291) Domain of hnRNPA2 and its D290V Mutation

Abstract

Recently, disorders in the function of hnRNPAs have been associated with many neurodegenerative diseases, especially amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, the fibrillation tendency of the low complexity (LC) domains of hnRNPAs is thought to be the root cause of these dysfunctions. In this paper, we present a molecular dynamic (MD) simulation study for the recently crystalized a fibril polymorph of the LC (286-291) domain (pdb id:6WPQ) of hnRNPA2 with the D290V mutation and its wild-type (WT) fibril form, that is no mutation. According to the MD simulation results, it was detected that fibril polymorph with D290V mutation has stable conformations, but WT is unstable for this fibril polymorph. As a result, the findings of the study indicate that only the D290V fibril structure can be considered as the target structure for possible future drug studies.

Keywords

Low complexity domain, molecular dynamic, simulation, D290V

Project Number

2015-22794455-03

References

• Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E, 2015. Gromacs: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers. SoftwareX, 1-2: 19-25.
• Alıcı H, Karacaoğlan V, Demir K, 2018. İnsan Kemokin Reseptörü CXCR3’ün N-Terminal Bölgesinin Moleküler Dinamik Simülasyon Yöntemi ile Modellenmesi ve Yapısal Analizi. Karaelmas Fen ve Mühendislik Dergisi, 8 (2): 606-614.
• Alıcı H, 2020. In Silico Analysis: Structural Insights About Inter-Protofilaments Interactions for Α-Synuclein (50–57) Fibrils and its Familial Mutation. Molecular Simulation, 46 (12): 867-878.
• Alred EJ, Scheele EG, Berhanu WM, Hansmann UH, 2014. Stability of Iowa Mutant and Wild Type A Β-Peptide Aggregates. The Journal of Chemical Physics, 141 (17): 175101.
• Amaya J, Ryan VH, Fawzi NL, 2018. The Sh3 Domain of Fyn Kinase Interacts with and Induces Liquid-Liquid Phase Separation of the Low-Complexity Domain of Hnrnpa2. The Journal of Biological Chemistry, 293 (51): 19522-19531.
• Berhanu WM, Hansmann UH, 2012. Side‐chain Hydrophobicity and the Stability of Aβ16–22 Aggregates. Protein Science, 21 (12): 1837-1848.
• Burd CG, Dreyfuss G, 1994. Rna Binding Specificity of Hnrnp A1: Significance of Hnrnp A1 High-Affinity Binding Sites in Pre-Mrna Splicing. The EMBO Journal, 13 (5): 1197-1204.
• Bussi G, Donadio D, Parrinello M, 2007. Canonical Sampling through Velocity Rescaling. The Journal of Chemical Physics, 126 (1): 014101.
• Darden T, York D, Pedersen L, 1993. Particle Mesh Ewald: An N⋅Log(N) Method for Ewald Sums in Large Systems. The Journal of Chemical Physics, 98 (12): 10089-10092.
• DeLano WL, 2002. Pymol: An Open-Source Molecular Graphics Tool. CCP4 Newsletter on protein crystallography, 40 (1): 82-92.
• Demir K, Alıcı H, Yaşar F, 2018. Conformational Stability of the Tetrameric De Novo Designed Hexcoil-Ala Helical Bundle. Chinese Journal of Physics, 56 (1); 46-57.
• Duan Y, Du A, Gu J, Duan G, Wang C, Gui X, Ma Z, Qian B, Deng X, Zhang K, Sun L, Tian K, Zhang Y, Jiang H, Liu C, Fang Y, 2019. Parylation Regulates Stress Granule Dynamics, Phase Separation, and Neurotoxicity of Disease-Related Rna-Binding Proteins. Cell Research, 29 (3): 233-247.
• Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG, 1995. A Smooth Particle Mesh Ewald Method. The Journal of Chemical Physics, 103 (19): 8577-8593.
• Fitzpatrick, AW, Debelouchina GT, Bayro MJ, Clare DK, Caporini MA, Bajaj VS, MacPhee CE, 2013. Atomic Structure and Hierarchical Assembly of a Cross-β Amyloid Fibril. Proceedings of the National Academy of Sciences, 110 (14): 5468-5473.
• Gilks N, Kedersha N, Ayodele M, Shen L, Stoecklin G, Dember LM, Anderson P, 2004. Stress Granule Assembly Is Mediated by Prion-Like Aggregation of Tia-1. Molecular Biology of The Cell, 15 (12): 5383-5398.
• Gomes E, Shorter J, 2019. The Molecular Language of Membraneless Organelles. The Journal of Biological Chemistry, 294 (18): 7115-7127.
• Gui X, Luo F, Li Y, Zhou H, Qin Z, Liu Z, Gu J, Xie M, Zhao K, Dai B, Shin WS, He J, He L, Jiang L, Zhao M, Sun B, Li X, Liu C, Li D, 2019. Structural Basis for Reversible Amyloids of Hnrnpa1 Elucidates Their Role in Stress Granule Assembly. Nature Communications, 10 (1): 2006.
• Guil S, Cáceres JF, 2007. The Multifunctional Rna-Binding Protein Hnrnp A1 Is Required for Processing of Mir-18a. Nature Structural & Molecular Biology, 14 (7): 591-596.
• Huang J, Rauscher S, Nawrocki G, Ran T, Feig M, de Groot BL, Grubmüller H, MacKerell AD, 2017. Charmm36m: An Improved Force Field for Folded and Intrinsically Disordered Proteins. Nature Methods, 14 (1): 71-73.
• Jain N, Lin H-C, Morgan CE, Harris ME, Tolbert BS, 2017. Rules of Rna Specificity of Hnrnp A1 Revealed by Global and Quantitative Analysis of Its Affinity Distribution. Proceedings of the National Academy of Sciences of the United States of America, 114 (9): 2206-2211.
• Jean-Philippe J, Paz S, Caputi M, 2013. Hnrnp A1: The Swiss Army Knife of Gene Expression. International Journal of Molecular Sciences, 14 (9): 18999-19024.
• Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML, 1983. Comparison of Simple Potential Functions for Simulating Liquid Water. The Journal of Chemical Physics, 79 (2): 926-935.
• Kato M, Han Tina W, Xie S, Shi K, Du X, Wu Leeju C, Mirzaei H, Goldsmith Elizabeth J, Longgood J, Pei J, Grishin Nick V, Frantz Douglas E, Schneider Jay W, Chen S, Li L, Sawaya Michael R, Eisenberg D, Tycko R, McKnight Steven L, 2012. Cell-Free Formation of Rna Granules: Low Complexity Sequence Domains Form Dynamic Fibers within Hydrogels. Cell, 149 (4): 753-767.
• Kim HJ, Kim NC, Wang Y-D, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi A-S, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP, 2013. Mutations in Prion-Like Domains in Hnrnpa2b1 and Hnrnpa1 Cause Multisystem Proteinopathy and Als. Nature, 495 (7442): 467-473.
• Lobanov MY, Bogatyreva NS, Galzitskaya OV, 2008. Radius of Gyration as an Indicator of Protein Structure Compactness. Molecular Biology, 42 (4): 623-628.
• Lu J, Cao Q, Hughes MP, Sawaya MR, Boyer DR, Cascio D, Eisenberg DS, 2020. Cryoem Structure of the Low-Complexity Domain of Hnrnpa2 and Its Conversion to Pathogenic Amyloid. Nature Communications, 11 (1): 4090-4090.
• Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP, 2015. Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization. Cell, 163 (1): 123-133.
• Parrinello M, Rahman A, 1981. Polymorphic Transitions in Single Crystals: A New Molecular Dynamics Method. Journal of Applied Physics, 52 (12): 7182-7190.
• Purice MD, Taylor JP, 2018. Linking Hnrnp Function to Als and Ftd Pathology. Frontiers in Neuroscience, 12: 326-326.
• White R, Gonsior C, Krämer-Albers E-M, Stöhr N, Hüttelmaier S, Trotter J, 2008. Activation of Oligodendroglial Fyn Kinase Enhances Translation of Mrnas Transported in Hnrnp A2-Dependent Rna Granules. The Journal of Cell Biology, 181 (4): 579-586.
• Xi W, Hansmann UH, 2017. Ring-like N-fold Models of Aβ 42 Fibrils. Scientific Reports, 7 (1): 1-14.
• Xiang S, Kato M, Wu LC, Lin Y, Ding M, Zhang Y, Yu Y, McKnight SL, 2015. The Lc Domain of Hnrnpa2 Adopts Similar Conformations in Hydrogel Polymers, Liquid-Like Droplets, and Nuclei. Cell, 163 (4): 829-839.
• Zheng J, Ma B, Tsai CJ, Nussinov R, 2006. Structural Stability and Dynamics of an Amyloid-forming Peptide GNNQQNY from the Yeast Prion Sup-35. Biophysical Journal, 91 (3): 824-833.