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Researchers Resolve Molecular Structure of Critical Ubiquitin-Binding Enzyme

By LabMedica International staff writers
Posted on 03 Feb 2016
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Image: Molecular model of E3 ubiquitin ligase (green), E2 ubiquitin enzyme (orange), \"activated ubiquitin\" (cyan), and \"allosteric ubiquitin\" (blue) (Photo courtesy of Dr. Bernhard Lechtenberg, Sanford Burnham Prebys Medical Discovery Institute).
Image: Molecular model of E3 ubiquitin ligase (green), E2 ubiquitin enzyme (orange), \"activated ubiquitin\" (cyan), and \"allosteric ubiquitin\" (blue) (Photo courtesy of Dr. Bernhard Lechtenberg, Sanford Burnham Prebys Medical Discovery Institute).
The molecular structure of a protein complex critically involved in diverse cellular functions such as cell signaling, DNA repair, and mounting anti-inflammatory and immune responses has been elucidated and presented in a recent paper.

Ubiquitination is a central process affecting all facets of cellular signaling and function. A critical step in ubiquitination is the transfer of the small regulatory protein ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate or a growing ubiquitin chain, which is mediated by E3 ubiquitin ligases.

Linear ubiquitin chains are important regulators of cellular signaling pathways that control innate immunity and inflammation through nuclear factor (NF)-kappaB activation and protection against tumor necrosis factor-alpha-induced apoptosis. They are synthesized by HOIP (ring finger protein 31), which belongs to the RBR (RING-between-RING) family of E3 ligases and is the catalytic component of LUBAC (linear ubiquitin chain assembly complex), a multisubunit E3 ligase.

Investigators at the Sanford Burnham Prebys Medical Discovery Institute (La Jolla, CA, USA) presented—for what might be the first time—the structure of the fully active human HOIP RBR in its transfer complex with an E2-ubiquitin conjugate, which elucidated the intricate nature of the RBR E3 ligases.

They reported in the January 20, 2016, online edition of the journal Nature that the active HOIP RBR adopted a conformation markedly different from that of auto-inhibited RBRs. Furthermore, RBR bound the E2~ubiquitin conjugate in an elongated fashion, with the E2 and E3 catalytic centers ideally aligned for ubiquitin transfer.

"We were surprised to find how the active form of the E3 ligase we analyzed, called HOIP, attaches ubiquitin in a markedly different way - an elongated fashion - compared to the other types of E3 ligases," said senior author Dr. Stefan Riedl, an associate professor in the NCI-designated Cancer Center at the Sanford Burnham Prebys Medical Discovery Institute. "This may be key to its role in activating the NF-kappaB pathway, a signaling process that is well established as a regulator of cell survival and death, and helps coordinate the immune system. NF-kappaB is the master regulator of inflammation inside cells, and its activation is believed to promote cancer development by inhibiting cell death and promoting inflammation. This study removes a significant technical barrier that has prevented exploiting RBR E3 ligases as a drug target for cancer and inflammatory disorders. Our next step is to continue to work very closely with our biology and immunology collaborators to more fully understand the regulation of RBR E3 ligases."

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Sanford Burnham Prebys Medical Discovery Institute


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