Molecular Recognition of PTS-1 Cargo Proteins by Pex5p: Implications for Protein Mistargeting in Primary Hyperoxaluria

Biomolecules

Noel Mesa-Torres²  Nenad Tomic³  Armando Albert¹  Eduardo Salido³  Angel L. Pey² 

[1] Departamento de Cristalografía y Biología Estructural, Instituto de Química-Física “Rocasolano”, Consejo Superior de Investigaciones Científicas, C/Serrano 119, 28006 Madrid, Spain; E-Mail:;Department of Physical Chemistry, Faculty of Sciences, University of Granada, Av. Fuentenueva s/n, 18071 Granada, Spain; E-Mail:;Center for Biomedical Research on Rare Diseases (CIBERER), University Hospital of the Canary Islands and CIBICAN, University of La Laguna, 38320 Tenerife, Spain; E-Mails:

关键词: peroxisomes;    protein import;    primary hyperoxaluria type I;    peroxin 5;    protein:protein interactions;    binding energetics;    structure-energetic correlations;   

DOI  :  10.3390/biom5010121

来源: mdpi

【 摘 要 】

Peroxisomal biogenesis and function critically depends on the import of cytosolic proteins carrying a PTS1 sequence into this organelle upon interaction with the peroxin Pex5p. Recent structural studies have provided important insights into the molecular recognition of cargo proteins by Pex5p. Peroxisomal import is a key feature in the pathogenesis of primary hyperoxaluria type 1 (PH1), where alanine:glyoxylate aminotransferase (AGT) undergoes mitochondrial mistargeting in about a third of patients. Here, we study the molecular recognition of PTS1 cargo proteins by Pex5p using oligopeptides and AGT variants bearing different natural PTS1 sequences, and employing an array of biophysical, computational and cell biology techniques. Changes in affinity for Pex5p (spanning over 3–4 orders of magnitude) reflect different thermodynamic signatures, but overall bury similar amounts of molecular surface. Structure/energetic analyses provide information on the contribution of ancillary regions and the conformational changes induced in Pex5p and the PTS1 cargo upon complex formation. Pex5p stability in vitro is enhanced upon cargo binding according to their binding affinities. Moreover, we provide evidence that the rational modulation of the AGT: Pex5p binding affinity might be useful tools to investigate mistargeting and misfolding in PH1 by pulling the folding equilibria towards the native and peroxisomal import competent state.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.