Ras-Efektör Etkileşimlerinin Yapısal Detaylarının Açığa Çıkarılması

Year 2019, , 90 - 99, 31.03.2019

Serena Muratcıoğlu Saliha Ece Acuner Özbabacan

https://doi.org/10.7240/jeps.528662

Abstract

Hücre zarıyla ilintili küçük Ras proteinleri pek
çok efektöre bağlanıp onları aktif hale getirerek hücre çoğalması, göçü,
hayatta kalma ve farklılaşması gibi çeşitli hücresel işlevleri kontrol ederler.
Ras üzerindeki mutasyonlar, yapısal olarak aktif proteine sebebiyet verir ve
insandaki birçok kanser tipinde tespit edilmişlerdir ve Ras topluluğu Ras’ı
hedef alan küçük moleküllü inhibitörler tasarlamak yerine Ras’ın efektör
yolaklarındaki protein-protein etkileşimlerini hedef alarak Ras’ın zar üzerindeki
lokalizasyonunu engellemeyi amaçlamaktadır. Ras’ın en çok çalışılan
efektörleri, Raf, PI3K ve RalGDS, Ras’a aynı yüzeyden bağlanmasına rağmen karşıt
sinyal yolaklarını ortaya çıkarırlar ve dolayısıyla hücrenin bu yolaklar
arasındaki zamansal ve mekansal kararları kritik öneme sahiptir. Ras/efektör
etkileşimlerinin yapısal detaylarını açığa çıkarmak, hücrenin karar
mekanizmasını anlamamıza ve protein-protein etkileşimlerini hassas olarak
hedeflememize yardımcı olabilir. Bununla birlikte, sadece birkaç Ras/efektör
kompleksinin kristal yapısı PDB'de bulunmaktadır. Bu çalışmada, Ras/efektör
komplekslerinin 3 boyutlu yapıları PRISM algoritması ile modellenmiştir ve Ras
üzerindeki sıcak nokta kalıntılarının yanı sıra önemli bağlanma bölgeleri
belirlenmiştir. Efektörler ayrıca, rekabetçi yolları ve "efektör
lobu" dışındaki bağlayıcı bölgeleri belirlemek için Ras'daki bağlayıcı
bölgelere göre sınıflandırılmıştır. Modellenen kompleksler, Ras ve ortakları
arasındaki arayüzeyler hakkında onkojenik Ras sinyal iletimini bloke etmek için
ilaç tasarım çalışmalarına rehberlik etme potansiyeli olan önemli bilgiler
ortaya koymaktadır.

Keywords

Ras efektörleri, onkojenik sinyal iletimi, protein-protein etkileşimi, protein-protein arayüzeyi, protein yapısı

Elucidating Structural Details of Ras-Effector Interactions

Abstract

Small
membrane-associated Ras proteins mediate a wide range of cellular functions, such as cell proliferation, migration,
survival, and differentiation; through binding
and activating numerous effectors. Constitutively
active mutant Ras proteins are detected in various types of human cancer and Ras community seeks approaches other
than small-molecule Ras inhibitors; such as targeting the protein-protein
interactions in the downstream Ras effector pathways and preventing its membrane localization. Although
the most studied effectors of Ras, i.e. Raf, PI3K and RalGDS, bind Ras through the
same site, they elicit opposing signaling pathways and thus, the temporal and
spatial decision of the cell among them is critical. Elucidating the structural
details of Ras/effector interactions can help us understand the cell decision
and target the protein-protein interactions precisely. However, only a few crystal
structures of Ras in complex with an effector are deposited in PDB. Here, the
3D structures of Ras/effector complexes were modeled with the PRISM algorithm and important binding sites as well as hot spot
residues on Ras were identified. The effectors were also classified according
to the binding regions on Ras, to determine the competitive pathways and the
binding regions other than the “effector lobe”. The
modeled complexes reveal important information about the interfaces between Ras
and its partners with the potential of guiding drug design studies to block oncogenic Ras signaling.

Keywords

Ras effectors, oncogenic signaling, protein-protein interaction, protein-protein interface, hot spot, protein structure

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