Characterization of CNPY5 and its family members

Danny Schildknegt, Naomi Lodder, Abhinav Pandey, Maarten Egmond, Florentina Pena, Ineke Braakman, Peter van der Sluijs*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The Canopy (CNPY) family consists of four members predicted to be soluble proteins localized to the endoplasmic reticulum (ER). They are involved in a wide array of processes, including angiogenesis, cell adhesion, and host defense. CNPYs are thought to do so via regulation of secretory transport of a diverse group of proteins, such as immunoglobulin M, growth factor receptors, toll-like receptors, and the low-density lipoprotein receptor. Thus far, a comparative analysis of the mammalian CNPY family is missing. Bioinformatic analysis shows that mammalian CNPYs, except the CNPY1 homolog, have N-terminal signal sequences and C-terminal ER-retention signals and that mammals have an additional member CNPY5, also known as plasma cell-induced ER protein 1/marginal zone B cell-specific protein 1. Canopy proteins are particularly homologous in four hydrophobic alpha-helical regions and contain three conserved disulfide bonds. This sequence signature is characteristic for the saposin-like superfamily and strongly argues that CNPYs share this common saposin fold. We showed that CNPY2, 3, 4, and 5 (termed CNPYs) localize to the ER. In radioactive pulse-chase experiments, we found that CNPYs rapidly form disulfide bonds and fold within minutes into their native forms. Disulfide bonds in native CNPYs remain sensitive to low concentrations of dithiothreitol (DTT) suggesting that the cysteine residues forming them are relatively accessible to solutes. Possible roles of CNPYs in the folding of secretory proteins in the ER are discussed.

Original languageEnglish
Pages (from-to)1276-1289
Number of pages14
JournalProtein Science
Volume28
Issue number7
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • B lymphocyte
  • Canopy (CNPY) proteins
  • CNPY5
  • ER
  • MZB1
  • pERp1
  • protein folding

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