Ras-Efektör Etkileşimlerinin Yapısal Detaylarının Açığa Çıkarılması

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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