Disease related single point mutations alter the global dynamics of a tetratricopeptide (TPR) α-solenoid domain

Salomé Llabrés (Lead / Corresponding author), Maxim I. Tsenkov, Stuart MacGowan, Geoffrey Barton, Ulrich Zachariae (Lead / Corresponding author)

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Abstract

Tetratricopeptide repeat (TPR) proteins belong to the class of α-solenoid proteins, in which repetitive units of α-helical hairpin motifs stack to form superhelical, often highly flexible structures. TPR domains occur in a wide variety of proteins, and perform key functional roles including protein folding, protein trafficking, cell cycle control and post translational modification. Here, we look at the TPR domain of the enzyme O-linked GlcNAc-transferase (OGT), which catalyses O-GlcNAcylation of a broad range of substrate proteins. A number of single-point mutations in the TPR domain of human OGT have been associated with the disease Intellectual Disability (ID). By extended steered and equilibrium atomistic simulations, we show that the OGT-TPR domain acts as an elastic nanospring, and that each of the IDrelated local mutations substantially affect the global dynamics of the TPR domain. Since the nanospring character of the OGT-TPR domain is key to its function in binding and releasing OGT substrates, these changes of its biomechanics likely lead to defective substrate interaction. We find that neutral mutations in the human population, selected by analysis of the gnomAD database, do not incur these changes. Our findings may not only help to explain the ID phenotype of the mutants, but also aid the design of TPR proteins with tailored biomechanical properties.
Original languageEnglish
Article number107405
Pages (from-to)1-8
Number of pages8
JournalJournal of Structural Biology
Volume209
Issue number1
Early online date16 Oct 2019
DOIs
Publication statusPublished - 1 Jan 2020

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