Title:An Analysis of Structure-function Co-relation between GLI Oncoprotein and HLA Immune-gene Transcriptional Regulation through Molecular Docking
Volume: 17
Issue: 4
Author(s): Durjoy Majumder*
Affiliation:
- Department of Physiology, West Bengal State University, Berunanpukuria, Malikapur, Barasat, 700 126 Kolkata,India
Keywords:
GLI, hedgehog signaling, HLA regulation, cancer, stemness, malignant cells.
Abstract:
Background: GLI proteins play a significant role in the transduction of the Hedgehog
(Hh) signaling pathway. A variety of human cancers, including the brain, gastrointestinal, lung,
breast, and prostate cancers, demonstrate inappropriate activation of this pathway. GLI helps in proliferation
and has an inhibitory role in the differentiation of hematopoietic stem cells. Malignancies
may have a defect in differentiation. Different types of malignancies and undifferentiated cells
have a low level of HLA expression on their cell surface.
Objective: Human Leukocytic Antigen (HLA) downregulation is frequently observed in cancer
cells. This work is aimed to hypothesize whether this downregulation of HLA molecules is GLI oncoprotein
mediated or not. To understand the roles of different types of GLI oncoproteins on different
classes of HLA transcriptional machinery was carried out through structure-based modeling
and molecular docking studies.
Methods: To investigate the role of GLI in HLA expression /downregulation is Hh-GLI mediated
or not, molecular docking based computational interaction studies were performed between different
GLI proteins (GLI1, GLI2, and GLI3) with TATA box binding protein (TBP) and compare the
binding efficiencies of different HLA gene (both HLA class I and –II) regulating transcription factors
(RelA, RFX5, RFXAP, RFXANK, CIITA, CREB1, and their combinations) with TBP. Due to
unavailability of 3D protein structures of GLI2 and cyclin D2 (a natural ligand of GLI1) were modelled
followed by structural validation by Ramachandran plot analysis.
Results: GLI proteins especially, GLI1 and GLI2, have almost similar binding energy of RFX5-RFXANK-
RFXAP and CIITA multi-protein complex to TBP but has lower binding energy between
RelA to TBP.
Conclusion: This study suggests that HLA class I may not be downregulated by GLI; however,
over-expression of GLI1 is may be responsible for HLA class II downregulation. Thus this protein
may be responsible for the maintenance of the undifferentiated state of malignant cells. This study
also suggests the implicative role of GLI1 in the early definitive stage of hematopoiesis.
