Structural Mapping of Missense Mutations in the Pex1/Pex6 Complex

International Journal of Molecular Sciences
Anne Schieferdecker, Petra Wendler

Abstract

Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. To date, no structural data are available for this AAA+ ATPase complex. However, a wealth of information can be transferred from low-resolution structures of the yeast scPex1/scPex6 complex and homologous, well-characterized AAA+ ATPases. We review the abundant records of missense mutations described in PBD patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. Several mutations concern functionally conserved residues that are implied in ATP hydrolysis and substrate processing. Contrary to fold destabilizing mutations, patients suffering from function-impairing mutations may not benefit from stabilizing agents, which have been reported as potential therapeutics for PBD patients.

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Citations

Oct 28, 2019·International Journal of Molecular Sciences·Ana G PedrosaJorge E Azevedo
Jan 6, 2021·Genes·Tung-Lin LeeChen-Chi Wu
Mar 31, 2021·Nature Structural & Molecular Biology·Saša Petrović, Petra Wendler

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Methods Mentioned

BETA
interaction studies
electron microscopy
two-hybrid
immunoprecipitation
protein folding

Software Mentioned

QUARK
Clustal Omega
iTASSER
Chimera
HHPred
EM
custom
R
JalView
MODELLER

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