Impact of Deamidation on the Structure and Function of Antiapoptotic Bcl-xL

Tanriver G., Monard G., ÇATAK Ş.

Journal of Chemical Information and Modeling, cilt.62, sa.1, ss.102-115, 2022 (SCI-Expanded, Scopus)

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 62 Sayı: 1
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1021/acs.jcim.1c00808
  • Dergi Adı: Journal of Chemical Information and Modeling
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Applied Science & Technology Source, Compendex, Computer & Applied Sciences, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.102-115
  • Boğaziçi Üniversitesi Adresli: Evet

Özet

Bcl-xL is an antiapoptotic mitochondrial trans-membrane protein, which is known to play a crucial role in the survival of tumor cells. The deamidation of Bcl-xL is a pivotal switch that regulates its biological function. The potential impact of deamidation on the structure and dynamics of Bcl-xL is directly linked to the intrinsically disordered region (IDR), which is the main site for post-translational modifications (PTMs). In this study, we explored deamidation-induced conformational changes in Bcl-xL to gain insight into its loss of function by performing microsecond-long molecular dynamics (MD) simulations. MD simulation outcomes showed that the IDR motion and interaction patterns have changed notably upon deamidation. Principal component analysis (PCA) demonstrates significant differences between wild-type and deamidated Bcl-xL and suggests that deamidation affects the structure and dynamics of Bcl-xL. The combination of clustering analysis, H-bond analysis, and PCA revealed changes in conformation, interaction, and dynamics upon deamidation. Differences in contact patterns and essential dynamics that lead to a narrowing in the binding groove (BG) are clear indications of deamidation-induced allosteric effects. In line with previous studies, we show that the IDR plays a very important role in the loss of apoptotic functions of Bcl-xL while providing a unique perspective on the underlying mechanism of Bcl-xL deamidation-induced cell death.