Sam domains are small (~70 aa long) protein binding modules that are rather versatile as concerning their functions and interaction properties. Sam domains fold in a five-helix bundle and tend to aggregate by forming homo and hetero-dimers, oligomers or even polymers. The EphA2 receptor presents a C-terminal Sam domain that is able to hetero-dimerize with the Sam domain from the lipid phosphatase Ship2 (Ship2-Sam) and the first Sam domain from the adaptor protein Odin (Odin-Sam1). Recruitment of Ship2 at the EphA2 receptor site is important to inhibit receptor endocytosis and consequent degradation and should mainly produce pro-oncogenic outcomes. Odin also plays a role in increasing receptor stability through its Sam domains.
EphA2 receptor levels are high in many types of cancers, being EphA2-Sam the site where modulators of receptor endocytosis and degradation are engaged, we believe that small molecules able to break heterotypic Sam-Sam interactions mediated by EphA2 may work as anticancer agents.
The structural details of the Ship2-Sam/EphA2-Sam and Odin-Sam1/EphA2-Sam interactions have been largely clarified during the past years. The two complexes adopt identical “Mid-Loop/End-Helix” interaction arrangements where the central regions of Ship2-Sam and Odin-Sam1 provide the Mid-Loop interface while the C-terminal helix and an adjacent loop form the End-Helix interface in EphA2-Sam.
1) Vincenzi M, Mercurio FA, Leone M. Sam Domains in Multiple Diseases. Curr Med Chem. 2020;27(3):450-476.doi: 10.2174/0929867325666181009114445.
2) Mercurio FA, Di Natale C, Pirone L, Vincenzi M, Marasco D, De Luca S, Pedone EM, Leone M. Exploring the Ability of Cyclic Peptides to Target SAM Domains: A Computational and Experimental Study. Chembiochem. 2020;21(5):702-711. doi:10.1002/cbic.201900444.
3) Mercurio FA, Di Natale C, Pirone L, Marasco D, Calce E, Vincenzi M, Pedone EM, De Luca S, Leone M. Design and analysis of EphA2-SAM peptide ligands: A multi-disciplinary screening approach. BioorgChem. 2019;84:434-443. doi: 10.1016/j.bioorg.2018.12.009.
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