Our Research

Polyubiquitination is crucial in controlling a number of cellular events. Polyubiquitins (polyUbs) are recognized by the functional diverse proteins with the ubiquitin-binding domain (UBD) to determine the signaling outcomes. During the past decade, many functional studies published in the high impact journals have pointed out that linear (M1-linked) polyUbs play a critical role in regulating the NF-κB signaling pathway. Excessive NF-κB activity has been linked to inflammatory disorders and autoimmune disease. We are interested in a M1-polyUbs binding protein family, the UBAN (ubiquitin-binding ABINs and NEMO) family, including NEMO, ABINs, and OPTN, which is crucial in mediating NF-kB signaling pathway. NEMO, a regulatory subunit of the IKK complex, acts as a positive regulator, whereas ABINs and OPTN play as a negative regulator in the NF-kB signaling. Among them, ABIN1 has been emerging as a preventer of inflammation and autoimmune to maintain immune homeostasis, which utilizes its UBAN domain to recognize linear (M1)-linked polyubiquitinated NF-κB activation mediators. PolyUb-mediated UBAN recruitment remains undetermined, since the recognition studies focused mostly on di-ubiquitin (diUb). The structural information of the detail molecular recognition mechanism for longer linear polyUbs is not well understood. How a polyUb promotes the interaction with ubiquitin-binding adaptors also remains largely unknown. Structural information for answering the questions is fundamentally important.

In our recent works, we have solved the crystal structures of the UBAN moiety of human ABIN1 in complex with M1-diUb, M1-triUb, and M1-tetraUb, respectively, and ABIN2 in complex with M1-triUb. We provide a glimpse of how a UBAN-containing protein interacts with a M1-polyUbs. The mutagenesis shows us how a M1-polyUb promotes higher-order assembly in interacting with the UBAN family members. In addition, our structural studies provide a general concept for a ubiquitin-binding protein like ABIN1 and ABIN2 containing two similar composite Ub binding surfaces that both the primary and secondary Ub-binding surfaces can cooperatively interact with an essential two tandem Ub moieties in a circumstance of high protein concentration as in cells during signal transduction. Our study further provides a structural-functional glimpse of M1-polyUb as a multiple-molecule binding platform to exert its intrinsic structural plasticity in mediating cellular signaling. The structural details of the molecular interaction may provide the knowledge for a potential drug design.