Ubiquitin transfer has been shown to be allosterically regulated:  Ubiquitin ligase (E3) RING domain binding to E2 at one site promotes ubiquitin release from the active site cysteine (~15� distance away) without substantial conformational change in E2. Previous studies used statistical coupling analysis to identify clusters of residues that might transmit information. We use a novel information-theory approach to identify residues with statistically significant correlated conformations in a set of equilibrium molecular dynamics simulations on the UBCH5B E2 protein. We observed substantial coupling between an E2's active site and its E3 RING domain binding site. Similar analysis was performed on the mutants I88A, I37A, controls P95A, K4A, and on the UBCH5B-E3 complex. With mutants, we observe that the pattern of correlations is disrupted, consistent with the experimental observation that these mutations abrogate the allostery in the UBCH5B E2. Significantly, we observe that the dynamics of the E2 active site is modulated by the E3 binding. This insight has relevance in developing strategies for inhibiting E2s.

Ubiquitin ligase binding modulates dynamics of the catalytic site of ubiquitin conjugating protein (E2): Insight into the structure and dynamics using computational tools

239th National Meeting (2010)

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