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While transcriptome- and proteome-wide technologies to assess processes in protein biogenesis are now widely available, we still lack global approaches to assay post-ribosomal biogenesis events, in particular those occurring in the eukaryotic secretory system. We here develop a method, SECRiFY, to simultaneously assess the secretability of >105 protein fragments by two yeast species, S. cerevisiae and P. pastoris, using custom fragment libraries, surface display and a sequencing-based readout. Screening human proteome fragments with a median size of 50–100 amino acids, we generate datasets that enable datamining into protein features underlying secretability, revealing a striking role for intrinsic disorder and chain flexibility. The SECRiFY methodology generates sufficient amounts of annotated data for advanced machine learning methods to deduce secretability patterns. The finding that secretability is indeed a learnable feature of protein sequences provides a solid base for application-focused studies. The exact protein features that control passage through the eukaryotic secretory system remain largely unknown. Here the authors report SECRiFY which they use to evaluate the secretory potential of polypeptides on a proteome-wide scale in yeast, revealing a role for flexibility and intrinsic disorder. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1038/s41467-021-26720-y. Correction to: I Nature Communications i https://doi.org/10.1038/s41467-021-26720-y, published online 05 November 2021 In this article the author name Wesley De Neve was incorrectly written as Wim De Neve. [Extracted from the article]