Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Abstract

Tumor Necrosis Factor Receptor Associated Factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system (CNS), and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. RING domain and zinc fingers mediate the activation of nuclear factor kappa B (NF-kB), which has essential roles in the regulation of inflammatory responses, proliferation, differentiation, migration, cell adhesion, and apoptosis. Therefore, it has been found that TRAF6 is overexpressed in various types of cancer including pancreatic, liver, lung, head and neck, breast, colorectal cancers, and melanoma along with inflammatory, autoimmune and neurodegenerative disorders. Furthermore, TRAF6 is an important therapeutic target for numerous disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we present a TRAF6 N-terminal structure determined at the Turkish Light Source Turkish DeLight to 2.6 A; resolution at cryogenic temperature. This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research.