Solution Structural Behavior of UBAN Domains Revealed by Coarse-Grained Computer Simulations

Proteins containing a Ubiquitin‐binding domain in ABIN and NEMO (UBAN) have a broad range of biological roles. Much of the control of ubiquitin recognition by individual UBAN‐domain containing proteins is based on protein structure. Ubiquitin recognition is further modulated by post‐translational modifications. X‐ray crystal structures of UBAN domains display coiled‐coil dimers in the absence or presence of M1‐linked ubiquitin. However, the solution structural behavior of these UBAN domains is not well understood. Extensive coarse‐grained molecular dynamics simulations of UBAN domains from NEMO, optineurin (OPTN), CEP55, and ABIN1 using a predictive energy landscape based model reveal unique signatures of solution structural conformational heterogeneity in NEMO and ABIN1 but a much more homogeneous distribution of highly extended OPTN conformations. Simulating phosphorylation of OPTN S473, a known post‐translational modification that increases M1‐linked ubiquitin affinity for OPTN, greatly increases OPTN conformational heterogeneity. Furthermore, phosphorylation of ABIN1 S442, a likely post‐translational modification in vivo , shifts the ABIN1 conformational distribution. These results indicate the conformational distribution of UBAN domains provides a means to tailor cellular response in specific biological roles, and post‐translational modifications in combination with conformational heterogeneity provide a rheostat‐like means to control cellular signaling pathways. Support or Funding Information This work was supported by internal funding from the University of Connecticut to James Halpert.