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)

Research output: Contribution to journalArticle

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
Number of pages8
JournalJournal of Structural Biology
Early online date16 Oct 2019
DOIs
Publication statusE-pub ahead of print - 16 Oct 2019

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Point Mutation
Proteins
Intellectual Disability
Mutation
Protein Folding
Protein Transport
Post Translational Protein Processing
Cell Cycle Checkpoints
Biomechanical Phenomena
O-GlcNAc transferase
Databases
Phenotype
Enzymes
Population

Cite this

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title = "Disease related single point mutations alter the global dynamics of a tetratricopeptide (TPR) α-solenoid domain",
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.",
author = "Salom{\'e} Llabr{\'e}s and Tsenkov, {Maxim I.} and Stuart MacGowan and Geoffrey Barton and Ulrich Zachariae",
note = "We gratefully acknowledge funding from the Wellcome Trust (ISSF award WT097818MF, SL and UZ), SUPA (Scottish Universities’ Physics Alliance, UZ) and the 4-year Wellcome Trust Doctoral Training Programme at the University of Dundee (MIT).",
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AU - Llabrés, Salomé

AU - Tsenkov, Maxim I.

AU - MacGowan, Stuart

AU - Barton, Geoffrey

AU - Zachariae, Ulrich

N1 - We gratefully acknowledge funding from the Wellcome Trust (ISSF award WT097818MF, SL and UZ), SUPA (Scottish Universities’ Physics Alliance, UZ) and the 4-year Wellcome Trust Doctoral Training Programme at the University of Dundee (MIT).

PY - 2019/10/16

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