Growth factors and hormones pro‐peptides: the unexpected adventures of the BDNF prodomain

Abstract

Most growth factors and hormones are synthesized as prepro-proteins which are processed to the biologically active mature protein. The pre-and prodomains are cleaved from the precursor protein in the secretory pathway or, in some cases, extracellularly. The canonical functions of these prodomains are to assist in folding and stabilization of the mature domain, to direct intra and extracellular localization, to facilitate storage, and to regulate bioavailability of their mature counterpart. Recently, exciting evidence has revealed that prodomains of certain growth factors, after cleaved from the precursor pro-protein, can act as independent active signaling molecules. In this review, we discuss the various classical functions of prodomains, and the biological consequences of these pro-peptides acting as ligands. We will focus our attention on the brain-derived neurotrophic factor prodomain (pBDNF), which has been recently described as a novel secreted ligand influencing neuronal morphology and physiology. Keywords: active prodomains, biosynthetic pathway, pBDNF, precursor cleavage peptides, proBDNF, Val66Met polymorphism. Most growth factors and hormones are synthetized as prepro-proteins. These prefixes are used to describe the intermediate processed forms of a protein before it is active and at the appropriate location. The prefix 'pre' indicates the presence of an N-terminal sequence that targets the precursor pro-protein to the secretory pathway or an intracellular compartment. For this reason, this sequence is referred to as 'signal peptide' or 'signal sequence'. Signal peptides, which are typically from 5 to 50 residues, are cleaved by signal peptidases and quickly degraded. Later, it was discovered that many proteins require additional proteolytic processing to become functional. This additional step involves cleavage of a subsequent N-terminal peptide, which is indicated by the prefix 'pro' accounting for prodomain (or pro-peptide; example in Fig. 1a). The processing of pro-proteins to remove their prodomains requires enzymes including proprotein convertases (or proconvertases), which are present in the Golgi apparatus or in secretory vesicles, or extracellular enzymes such as matrix metalloproteinases among others. For example, the pro-protein of the neurotrophin brainderived neurotrophic factor (proBDNF), can be cleaved by furin and other proconvertases in the trans-Golgi network or Received December 29, 2016; revised manuscript received February 8, 2017; accepted February 13, 2017. Address correspondence and reprint requests to Agustin Anastasia, Instituto de Investigaci on M edica Mercedes y Martin Ferreyra, (INIMEC-CONICET-Universidad Nacional de C ordoba), Friuli 2434, C ordoba, C ordoba 5016, Argentina. E-mail: aanastasia@immf.uncor.edu.Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BMP, bone morphogenetic protein; CD, circular dichroism; DNSP, dopamine neuron-stimulating peptide; GDNF, glial cell line-derived neurotrophic factor; GPR146, G-prote...

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