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.

Goal

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