Structural Mapping of Missense Mutations in the Pex1/Pex6 Complex
- 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 forPeroxisome 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.…
| Author details: | Anne Schieferdecker, Petra WendlerORCiDGND |
|---|---|
| DOI: | https://doi.org/10.3390/ijms20153756 |
| ISSN: | 1422-0067 |
| Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/31374812 |
| Title of parent work (English): | International journal of molecular sciences |
| Publisher: | MDPI |
| Place of publishing: | Basel |
| Publication type: | Article |
| Language: | English |
| Date of first publication: | 2019/08/01 |
| Publication year: | 2019 |
| Release date: | 2021/01/07 |
| Tag: | Pex1; Pex6; Zellweger; Zellweger syndrome spectrum disorder (ZSSD); mutation; structure |
| Volume: | 20 |
| Issue: | 15 |
| Number of pages: | 25 |
| Funding institution: | DFG (Deutsche Forschungsgemeinschaft)German Research Foundation (DFG) [WE4628/3-1] |
| Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
| DDC classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
| Peer review: | Referiert |
| Publishing method: | Open Access / Gold Open-Access |
| DOAJ gelistet | |
| License (German): |  CC-BY - Namensnennung 4.0 International |
| External remark: | Zweitveröffentlichung in der Schriftenreihe Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe ; 1072 |
