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Terminal Peptide Extensions Augment the Retinal IMPDH1 Catalytic Activity and Attenuate the ATP-induced Fibrillation Events

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Abstract

Defects in inosine monophosphate dehydrogenase-1 (IMPDH1) lead to insufficient biosyntheses of purine nucleotides. In eyes, these defects are believed to cause retinitis pigmentosa (RP). Major retinal isoforms of IMPDH1 are structurally distinct from those in other tissues, by bearing terminal extensions. Using recombinant mouse IMPDH1 (mH1), we evaluated the kinetics and oligomerization states of the retinal isoforms. Moreover, we adopted molecular simulation tools to study the possible effect of terminal tails on the function of major enzyme isoforms with the aim to find structural evidence in favor of contradictory observations on retinal IMPDH1 function. Our findings indicated higher catalytic activity for the major mouse retinal isoform (mH1603) along with lower fibrillation capacity under the influence of ATP. However, higher mass oligomerization products were formed by the mH1 (603) isoform in the presence of the enzyme inhibitors such as GTP and/or MPA. Collectively, our findings demonstrate that the structural differences between the retinal isoforms have led to functional variations possibly to justify the retinal cells’ requirements.

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Acknowledgements

This work was supported by the Research Council of University of Tehran, and Iranian National Science Foundation (INSF) under the project #94020269.

Author contributions

B.A. performed the experimental analyses and assisted in writing the paper, R.Y. supervised the research, designed the experiments and editted the manuscript, M.M. performed a part of experimental analyses, E B. done the bioinformatics model analysis and participated in the manuscript preparation and H.G. analyzed the molecular genetics data and sequences.

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Research Council of University of Tehran.

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Authors and Affiliations

  1. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    Behnaz Andashti, Razieh Yazdanparast, Maede Motahar & Ebrahim Barzegari

  2. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran

    Hamid Galehdari

  3. Biotechnology and Biological Science Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran

    Hamid Galehdari

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  1. Behnaz Andashti
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  2. Razieh Yazdanparast
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  3. Maede Motahar
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  4. Ebrahim Barzegari
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  5. Hamid Galehdari
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Correspondence to Razieh Yazdanparast.

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Andashti, B., Yazdanparast, R., Motahar, M. et al. Terminal Peptide Extensions Augment the Retinal IMPDH1 Catalytic Activity and Attenuate the ATP-induced Fibrillation Events. Cell Biochem Biophys 79, 221–229 (2021). https://doi.org/10.1007/s12013-021-00973-2

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