Mechanistic influence of discreet conformation of human telomerase linker region

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Human telomerase activity is present in approximately 90% of malignancies, making it a key therapeutic target.
• The recent crystal structure of telomerase leaves the tertiary structure of its non-conserved flexible linker region unresolved.

Purpose of the Study:

• To predict the full-length tertiary structure of human telomerase reverse transcriptase (hTERT).
• To analyze the structural characteristics and flexibility of the hTERT linker region.

Main Methods:

• Employed two strategies: iterative threading and a conjoined model using machine learning and energy functions.
• Utilized energy minimization, Ramachandran Plot analysis, and molecular dynamics simulation for model validation.

Main Results:

• The conjoined model demonstrated superior quality and stability compared to the iterative threading model.
• The hTERT linker region in the conjoined model featured two distinct helices, unlike the single helix in the threading model.
• Significant structural dynamics were observed in the linker region during simulation, indicating high flexibility.

Conclusions:

• The conjoined model provides a more accurate and stable prediction of the full-length hTERT structure.
• The flexible linker region, characterized by glycine and proline residues, may play a role in enhancing telomerase's clamping movement.
• Understanding hTERT's flexible regions offers new insights for developing targeted cancer therapies.