Biology:Preproinsulin

Ribosomes feed the growing amino acid chain (preproinsulin) directly into the ER where the signal peptide (red) is immediately cleaved off by the signal peptidase (red triangle) to yield proinsulin. This is later processed further to mature and active insulin. Cell components and proteins in this image are not to scale.

Preproinsulin is the primary translational product of the INS gene. It is a peptide that is 110 amino acids in length. Preproinsulin is a proinsulin molecule with a signal peptide attached to its N-terminus.

Insulin synthesis pathway

Preproinsulin is a biologically inactive precursor to the biologically active endocrine hormone insulin. Preproinsulin is converted into proinsulin by signal peptidases, which remove its signal peptide from its N-terminus. Finally, proinsulin is converted into the bioactive hormone insulin by removal of the C-peptide.

Almost no preproinsulin exists in the cell, because removal of the signal peptide is not a separate step, but rather is closely linked to translocation of the protein into the endoplasmic reticulum (ER). For the same reason, preproinsulin is rarely used medicinally, unlike insulin, the mature product, and proinsulin, a stable ER intermediate.

History

• Dr. Hans E. Weber discovered preproinsulin while working as a research fellow at the University of California Los Angeles in 1974.  In 1973-1974, Dr. Weber learned the techniques of how to isolate, purify, and translate messenger RNA.  To further investigate insulin, he obtained pancreatic tissues from a slaughterhouse in Los Angeles and then later from animal stock at UCLA.  He isolated and purified total messenger RNA from pancreatic islet cells which was then translated in oocytes from Xenopus laevis and precipitated using anti-insulin antibodies.  When total translated protein was run on an SDS-polyacrylamide gel electrophoresis and sucrose gradient, peaks corresponding to insulin and proinsulin were isolated.  However, to the surprise of Dr. Weber a third peak was isolated corresponding to a molecule larger than proinsulin.  After reproducing the experiment several times, he consistently noted this large peak prior to proinsulin that he determined must be a larger precursor molecule upstream of proinsulin.  In May of 1975, at the American Diabetes Association meeting in New York, Dr. Weber gave an oral presentation of his work (1) where he was the first to name this precursor molecule “preproinsulin”.  Following this oral presentation, Dr. Weber was invited to dinner to discuss his paper and findings by Dr. Donald Steiner, a researcher who contributed to the characterization of proinsulin.  A year later in April 1976, this molecule was further characterized and sequenced by Dr. Donald Steiner, referencing the work and discovery of Dr. Hans Weber (2).  Preproinsulin became an important molecule to study the process of transcription and translation.
  1. Weber, H.E. (1975) Diabetes 24, 405. (see figure)
  2. Chan SJ, Keim P, Steiner DF.  Cell-free synthesis of rat preproinsulins: Characterization and partial amino acid sequence determination.  Proc Natl Acad Sci. USA 1976;73:1964-1968.

preproinsulin definition in the glossary of the Beta Cell Biology Consortium

Proprotein convertase 1, proprotein convertase 2