Although extensive studies have been performed on Neurofibromatosis type I from a genetic and phenotypic point of view, NF1 still suffers from a lack of efficient targeted treatment. To develop new innovative therapies, it appears crucial to have a better understanding of Neurofibromin, Nf1, the protein encoded by the NF1 gene, from a molecular point of view. We are especially interested in SUMOylation (Small Ubiquitin-related Modifier), a versatile and dynamic Post Translational Modification (PTM) involved in the regulation of nearly all cellular pathways and which is frequently defective in neurodegenerative disorders and correlates with resistance to cancer treatment when constitutively increased. We have previously shown that Nf1 partially colocalized with the ProMyelocytic Leukemia (PML) protein in PML nuclear bodies, which are hotspots of SUMOylation. Here, we demonstrate that the full-length isoform 2 and a SecPH fragment of Nf1 are substrates of the SUMO pathway, and we identify a well-defined SUMOylation profile of SecPH with two main modified Lysines. One of these sites, K1731, is highly conserved and surface-exposed. We show that well-described SUMOylation mechanisms are not required for K1731 SUMOylation. On the opposite, structure-guided mechanistic hypotheses combined with site-directed mutagenesis identify specific unusual structural elements of SecPH required for K1731 SUMOylation. Some of these elements are affected in reported NF1 pathogenic variants. This work describes for the first time the SUMOylation of Nf1 and depicts in details its mechanism providing one of the rare examples of SUMOylation dependent on the tertiary rather than primary protein structure surrounding the modified site, opening the path to a better understanding of Nf1 from a molecular point of view. This new perspective is highlighted in a second/an accompagning poster (HB) whereby SecPH SUMOylation studies of NF1 specific missense variants helped us to decipher the molecular mechanism underlying their pathogenicity.