Large precursor proteins encoding one or more active peptides or polypeptide chains are referred to as polyproteins. Polyproteins are synthesized on ribosomes in the normal method of protein biosynthesis, transported into the lumen of the rough endoplasmic reticulum (ER) and then transported to the Golgi apparatus, where they are sorted into secretory vesicles. In this process, the proteins undergo a series of posttranslational modifications and are processed into multiple copies of the same peptide or into different polypeptides or proteins. Thus many peptide growth hormones (see Peptide Hormones) and signaling peptides are cleaved proteolytically from their precursor prohormones by endoproteinases at basic residues or pairs of basic residues at the recognition sequence. This often occurs in the secretory granules or vesicles, prior to exocytosis. Furthermore, the differential processing of the polyprotein in various tissues often leads to different sets of products (1).
For example, pro-opiomelanocortin (POMC) is a 32-kDa polyprotein that is processed to adrenocorticotropic hormone (ACTH ) and b-lipotropin (b-LPH ) in the corticotrophic cells of the anterior pituitary under the control of corticotropin -releasing hormone (CRH). However, alpha-melanocyte-stimulating hormone (a-MSH ), corticotropin-like intermediary peptide (CLIP), g-lipotropin, and b-endorphin are the products generated in the intermediary pituitary under the control of dopamine (2) (see Fig. 1 of Peptide Hormones). Like many translation products, polyproteins also contain a signal peptide for transport into the ER that is cleaved before processing. In another type of polypeptide processing, multiple copies of enkephalin are contained within the enkephalin precursor
Other examples of polyproteins are found in the translation products of viruses. Production of the infectious human immunodeficiency virus ( HIV), for example, requires proper polyprotein processing by the dimeric HIV viral proteinase to activate it. Other viral polyproteins include those of the hepatitis A, C, and G, rubella, dengue, poliovirus, foot and mouth disease, and yellow fever viruses. These polyproteins not only play a role in infection and disease, but they may be of use in gene therapy. Viral vectors are now being investigated as a means of expressing and delivering peptide drugs to patients with deficiencies or genetic mutations (4).
Likewise, hybrid genes in transgenic animals can control synthesis of human polyproteins that can be isolated from milk, subsequently processed into human proteins, and used as therapeutic drugs (5).
