Preproproteins

Preproproteins are precursor polypeptides that contain both an N-terminal signal sequence (the “pre”) and an additional pro region (the “pro”) that must be removed to generate a mature, active protein. They are characteristic of many secreted and membrane proteins, including hormones, enzymes, and receptors. The pre sequence directs the growing peptide to the secretory pathway, and the pro region often assists in folding, stability, and trafficking before final activation.

Biogenesis begins in the cytosol with translation of the preproprotein. The short signal peptide is recognized by the signal recognition particle (SRP), guiding the ribosome–polypeptide complex to the endoplasmic reticulum (ER). The signal peptide is cleaved by signal peptidase, yielding a proprotein that continues through the secretory pathway. Throughout folding and maturation, chaperones and disulfide bond formation help achieve the correct conformation.

Processing to mature protein typically occurs in the secretory pathway via proteolytic cleavage of the pro region by specific proteases, such as proprotein convertases. This step can generate multiple active products from a single proprotein, as seen with proinsulin being processed to insulin and C-peptide, or proopiomelanocortin (POMC) being cleaved into several peptide hormones. In some cases, the pro region remains part of the mature protein or serves as an inhibitory segment until activation.

Localization after processing varies: mature proteins may be secreted, inserted into cellular membranes, or retained in cellular organelles. Preproproteins thus exemplify how initial translation products undergo ordered processing to yield diverse, functional biomolecules. Their study illuminates hormone maturation, enzyme activation, and protein trafficking, with implications for endocrinology and related diseases.