National Institute of Immunology found substitution of α-helix with a flexible peptide as linker protein for enhanced GMP formation

National Institute of Immunology (NII), New Delhi’s scientists found that substitution of the helix with a flexible peptide sequence in the full-length hGBP-1 (termed as linker protein) effective in GMP formation. Unlike wild-type, the linker protein is not capable of undergoing substrate-induced oligomerization, suggesting the importance of the helix in oligomerization during the GTP hydrolysis.

Furthermore, they examined the effect of interactions between this helix and the α2-helix of the globular domain in GMP formation through mutational studies. A single residue mutation (L118G) in the α2-helix showed a significantly reduced GMP formation, indicating that the interactions of the α-helix with the α2-helix are essential for enhanced GMP production. It was proposed that these interactions may help in the oligomerization-assisted proper positioning of the catalytic machinery for efficient second phosphate cleavage. Thus, the helix of the intermediate region may act as a ‘coupler’ or ‘relay arm’, which transmits conformational changes between the two domains during oligomerization, thereby regulating GMP formation.

These findings provide a better understanding into the regulation of GMP formation in a large GTPase hGBP-1. The interferon-gamma inducible large GTPase human guanylate binding protein-1 (hGBP-1) plays key role in anti-pathogenic and anti-proliferative functions. The hGBP-1 protein hydrolyzes GTP to GMP through successive phosphate cleavages, which makes it functionally distinct from other known GTPases. The enhanced GMP formation of this enzyme is associated with biological functions. It is a 592-residues long protein consisting of the two domains, an Nterminal globular- and a C-terminal helical domain, which are linked by an intermediate region  comprising a β-sheet and an α-helix. The role of the helix in the intermediate region of the fulllength protein in GMP formation was not clearly understood.

Publication: Sudeepa Rajan 1Apurba Kumar Sau 2 ,The Alpha Helix of the Intermediate Region in hGBP-1 Acts as a Coupler for Enhanced GMP Formation. Biochim Biophys Acta Proteins Proteom, 2020 May;1868(5):140364.  

doi: 10.1016/j.bbapap.2020.140364. Epub 2020 Jan 16.

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