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

Year 2021, , 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

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