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bioRxiv · 10.1101/2023.05.30.542994

Structure of puromycin-sensitive aminopeptidase and polyglutamine binding

Madabushi, S.·Chow, K. M.·Song, E. S.·Goswami, A.·Hersh, L. B.·Rodgers, D. W.
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Abstract

Puromycin-sensitive aminopeptidase (E.C. 3.4.11.14, UniProt P55786), a zinc metallopeptidase belonging to the M1 family, degrades a number of bioactive peptides as well as peptides released from the proteasome, including polyglutamine. We report the crystal structure of PSA at 2.3 A'. Overall, the enzyme adopts a V-shaped architecture with four domains characteristic of the M1 family aminopeptidases, but it is in a less compact conformation compared to most M1 enzymes of known structure. A microtubule binding sequence is present in a C-terminal HEAT repeat domain of the enzyme in a position where it might serve to mediate interaction with tubulin. In the catalytic metallopeptidase domain, an elongated active site groove lined with aromatic and hydrophobic residues and a large S1 subsite may play a role in broad substrate recognition. The structure with bound polyglutamine shows a possible interacting mode of this peptide, which is supported by mutation.

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Madabushi, S., Chow, K. M., Song, E. S., Goswami, A., Hersh, L. B., Rodgers, D. W.. 2023-06-01. Structure of puromycin-sensitive aminopeptidase and polyglutamine binding. https://doi.org/10.1101/2023.05.30.542994

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