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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/45012

Title: Molecular Recognition of PTS-1 Cargo Proteins by Pex5p: Implications for Protein Mistargeting in Primary Hyperoxaluria
Authors: Mesa-Torres, Noel
Tomic, Nenad
Albert, Armando
Salido, Eduardo
Pey, Ángel L.
Issue Date: 2015
Abstract: 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.
Publisher: MDPI
Keywords: Peroxisomes
Protein import
Primary hyperoxaluria type I
Peroxin 5
Protein interactions
Biding energetics
Structura-energetic correlations
URI: http://hdl.handle.net/10481/45012
ISSN: 2218-273X
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: Mesa-Torres, N. [et al]. Molecular Recognition of PTS-1 Cargo Proteins by Pex5p: Implications for Protein Mistargeting in Primary Hyperoxaluria. Biomolecules 2015, 5, 121-141. [http://hdl.handle.net/10481/45012]
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