Two Dipolar a-Helices Within Hormone-Encoding Regions of Proglucagon are Sorting Signals to the Regulated Secretory Pathway.

The Journal of biological chemistry

PubMedID: 24727476

Guizzetti L, McGirr R, Dhanvantari S. Two Dipolar a-Helices Within Hormone-Encoding Regions of Proglucagon are Sorting Signals to the Regulated Secretory Pathway. J Biol Chem. 2014;.
Proglucagon is expressed in pancreatic a cells, intestinal L cells, and some hypothalamic and brainstem neurons. Tissue-specific processing of proglucagon yields three major peptide hormones: glucagon in the a cells, and glucagon-like peptides (GLP)-1 and -2 in the L cells and neurons. Efficient sorting and packaging into the secretory granules of the regulated secretory pathway in each cell type is required for nutrient-regulated secretion of these proglucagon-derived peptides (PGDPs). Our previous work suggested that proglucagon is directed into granules by intrinsic sorting signals after initial processing to glicentin and major proglucagon fragment (MPGF) (McGirr et al. J. Endocrinol. 2013), leading to the hypothesis that sorting signals may be present in multiple domains. In the present study, we show that the a-helices within glucagon and GLP-1, but not GLP-2, act as sorting signals by efficiently directing a heterologous secretory protein to the regulated secretory pathway. Biophysical characterization of these peptides revealed that glucagon and GLP-1 each encode a non-amphipathic, dipolar a-helix, while the helix in GLP-2 is not dipolar. Surprisingly, glicentin and MPGF were sorted with different efficiencies, thus providing evidence that proglucagon is first sorted to granules prior to processing. In contrast to many other prohormones in which sorting is directed by ordered prodomains, the sorting determinants of proglucagon lie within the ordered hormone domains of glucagon and GLP-1, illustrating that each prohormone has its own sorting "signature."