Insights into the interaction of sortilin with proneurotrophins: a computational approach.
Sortilin is a member of the recently discovered family of type-1 transmembrane Vps10p-domain receptors, which are expressed in several tissues, including brain and spinal chord. It has been recently demonstrated that the interaction between sortilin and the N-terminal portion of the precursor forms of the nerve growth factor (pro-NGF) and the brain-derived neurotrophic factor (pro-BDNF) represents a key event in the process that controls neurotrophins-mediated cell survival and death in developing neuronal tissue and post-traumatic neuronal apoptosis. Moreover, it is known that the cleavage of the N-terminal propeptide of sortilin is required for full functional activity of the receptor. The propeptide, indeed, hinders ligands from accessing the binding site of sortilin. However, to date, the molecular mechanism underlying the interaction between sortilin and pro-NGF/pro-BDNF remains unknown. By means of computational approaches, we suggest that the N-terminal Vps10p domain of sortilin, which is responsible for the interaction with the neurotrophins, adopts a beta-propeller fold, and that the N-terminal regions of sortilin, pro-NGF and pro-BDNF are mainly intrinsically disordered regions (IDRs). The following mechanism is therefore proposed: the Vps10p-domain of sortilin is a beta-propeller able to bind its own IDR and the IDRs of neurotrophins. The excision of its N-terminal disordered peptide allows the interaction with the intrinsically disordered N-terminus of pro-BDNF and pro-NGF, possibly through a disorder-to-order transition behaviour.
Paiardini
Alessandro
A
Dipartimento di Scienze Biochimiche A. Rossi Fanelli, Università di Roma La Sapienza, Piazzale Aldo Moro 5, Via degli Apuli 9, 00185 Rome, Italy. alessandro.paiardini@uniroma1.it
Caputo
Viviana
V
D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry / Q000378:metabolism*; D019295:Computational Biology; D030562:Databases, Protein; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D008024:Ligands; D008562:Membrane Glycoproteins; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D000099183:Sortilin; C061397:pro-nerve growth factor, human