Signal Peptide-rheostat Dynamics Delay Secretory Preprotein Folding

•Higher hydrophobicity drives partial helical structure formation in signal peptides.•Partially helical structured signal peptide elevate dynamics in mature domain linkers.•Highly hydrophobic signal peptides block mature domain folding and enhance secretion.•Signal peptide effects are guided via their flexible C-region and the rheostat (cis).•The rheostat also plays a role in guiding mature domain folding.