Human Type I DNA Topoisomerase: Regulation of Expression and Function

There is an increased interest and more studies highlight the fact that bone strength depends not only on bone tissue quantity, but also on its quality, which is characterized by the geometry and shape of bones, trabecular bone microarchitecture, mineral content, organic matrix and bone turnover. Fibrillar type I collagen is the major organic component of bone matrix, providing form and a stable template for mineralization. The biomedical importance of collagen as a biomaterial for medical and cosmetic purposes and the improvement of the molecular, cellular biology and analytical technologies, led to increasing interest in establishing the structure of this protein and in setting of the relationships between sequence, structure, and function. Bone collagen crosslinking chemistry and its molecular packing structure are considered to be distinct features. This unique post-translational modifications provide to the fibrillar collagen matrices properties such as tensile strength and viscoelasticity. Understanding the complex structure of bone type I collagen as well as the dynamic nature of bone tissues will help to manage new therapeutic approaches to bone diseases.

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A reverse gyrase with an unusual structure. A type I DNA topoisomerase from the hyperthermophile Methanopyrus kandleri is a two-subunit protein

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)78094-6 ◽

1994 ◽

Vol 269 (15) ◽

pp. 11081-11089

Author(s):

S.A. Kozyavkin ◽

R. Krah ◽

M. Gellert ◽

K.O. Stetter ◽

J.A. Lake ◽

...

Keyword(s):

Type I ◽

Reverse Gyrase ◽

Unusual Structure ◽

Dna Topoisomerase ◽

Subunit Protein ◽

Methanopyrus Kandleri

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Molecular and Pharmacological Characterization of the Interaction between Human Geranylgeranyltransferase Type I and Ras-Related Protein Rap1B

International Journal of Molecular Sciences ◽

10.3390/ijms22052501 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2501

Author(s):

Sonja Hinz ◽

Dominik Jung ◽

Dorota Hauert ◽

Hagen S. Bachmann

Keyword(s):

Protein Function ◽

Tumor Development ◽

Cysteine Residue ◽

Type I ◽

Pharmacological Characterization ◽

Anti Cancer ◽

And Function ◽

Caax Motif ◽

Important Drug

Geranylgeranyltransferase type-I (GGTase-I) represents an important drug target since it contributes to the function of many proteins that are involved in tumor development and metastasis. This led to the development of GGTase-I inhibitors as anti-cancer drugs blocking the protein function and membrane association of e.g., Rap subfamilies that are involved in cell differentiation and cell growth. In the present study, we developed a new NanoBiT assay to monitor the interaction of human GGTase-I and its substrate Rap1B. Different Rap1B prenylation-deficient mutants (C181G, C181S, and ΔCQLL) were designed and investigated for their interaction with GGTase-I. While the Rap1B mutants C181G and C181S still exhibited interaction with human GGTase-I, mutant ΔCQLL, lacking the entire CAAX motif (defined by a cysteine residue, two aliphatic residues, and the C-terminal residue), showed reduced interaction. Moreover, a specific, peptidomimetic and competitive CAAX inhibitor was able to block the interaction of Rap1B with GGTase-I. Furthermore, activation of both Gαs-coupled human adenosine receptors, A2A (A2AAR) and A2B (A2BAR), increased the interaction between GGTase-I and Rap1B, probably representing a way to modulate prenylation and function of Rap1B. Thus, A2AAR and A2BAR antagonists might be promising candidates for therapeutic intervention for different types of cancer that overexpress Rap1B. Finally, the NanoBiT assay provides a tool to investigate the pharmacology of GGTase-I inhibitors.

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