The human proto-oncoprotein AF4 interacts with the E3-ligases SIAH1 and SIAH2

The human proto-oncoprotein AF4 was identified to interact with SIAH1 and SIAH2. SIAH proteins belong to the family of ubiquitin E3 ligases that bind to specific target proteins and mediate their destruction via the proteasomal pathway. Therefore, SIAH target proteins are strictly controlled in their specific steady-state level and their turn-over rates. Currently known SIAH target proteins are e.g. DCC, OBF1, TIEG1, Numb, Vav1, NcoR, PML, TCTP and CtIP, which are all degraded by the SIAH system. By contrast, Bag1 and Disabled bind SIAH proteins and block their biological function. We have analyzed which portion of AF4 is binding to SIAH proteins and what is the biological consequence of this specific interaction. The minimal contact sites in both proteins were characterized. Only a small N-terminal portion of AF4 is necessary to bind to the antiparallel ß-sheets of the C-terminus of both SIAH proteins. The minimal contact domain in AF4 exhibits the same signature as other known SIAH target proteins. Transfection studies revealed that AF4 is a target protein of the SIAH-mediated proteosomal degradation pathway. The biological consequences of the SIAH/AF4 protein interaction will be discussed.

Supported by grant Ma 1876/4–1 from the DFG.