Prof Danny Huang - Ubiquitin Signalling

Introduction

Huang head 069

Post-translational modifications of ubiquitin and ubiquitin-like proteins (Ubls) control myriad of cellular processes ranging from cell cycle regulation, transcription and DNA repair to virus budding. Ubls are attached to protein targets by a hierarchical cascade of enzymes involving an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase.

Defects in these pathways have been associated with diseases such as cancer, neurodegenerative disorder and viral infection. Bortezomib (Velcade) targets ubiquitin-proteasome system, is presently approved for treating multiple myeloma demonstrating the importance of the ubiquitin-proteasome pathway in anti-cancer therapies.

E3s promote transfer of Ub from E2 to the amino group of a substrate lysine, and thus play a pivotal role in determining substrate fate. In general, E3s contain an E2 binding module (HECT, RING, U-box and RING-in-between-RING) and a substrate-binding domain to facilitate Ub transfer. RING E3s are the largest class with ~600 members in the human genome. Our group applies X-ray crystallography and biochemical approaches to study the regulation, mechanistic functions and mutation-induced deregulation in RING E3s.

See more about Prof Huang's work on Cbl on the Protein Data Bank website.

Other funding:

Lab Report

Huang Lab Report (687 KB)

Key Publications

Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sibbet GJ, Smith BO, Zhang W, Sidhu SS, Huang DT. A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants. Mol Cell 2017; 68: 456-70 e10

Nomura K, Klejnot M, Kowalczyk D, Hock AK, Sibbet GJ, Vousden KH, Huang DT. Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity. Nat Struct Mol Biol 2017; 24: 578-87

Buetow L, Gabrielsen M, Anthony NG, Dou H, Patel A, Aitkenhead H, Sibbet GJ, Smith BO, Huang DT. Activation of a primed RING E3-E2-ubiquitin complex by non-covalent ubiquitin. Molecular Cell 58: 297-310, 2015

Dou H, Buetow L, Sibbet GJ, Cameron K, Huang DT. Essentiality of a non-RING element in priming donor ubiquitin for catalysis by a monomeric E3. Nat Struct Mol Biol 20: 982-6, 2013

Dou H, Buetow L, Sibbet GJ, Cameron K, Huang DT. BIRC7-E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nature Structural and Molecular Biology 19: 876-83, 2012 (News and Views, Nature 489, 43-4)

Dou H, Buetow L, Hock A, Sibbet GJ, Vousden KH, Huang DT. Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nature Structural and Molecular Biology 19: 184-92, 2012 (News and Views, Nature Structural and Molecular Biology 19, 131-3)

Huang DT, Ayrault O, Hunt HW, Taherbhoy AT, Duda DM, Scott DC, Borg LA, Neale G, Murray PJ, Roussel MF, Schulman BA. E2-RING expansion of the NEDD8 cascade confers specificity to Cullin modification. Molecular Cell 33: 483-95, 2009

Huang DT, Zhuang M, Schulman BA. Identification of conjugation specificity determinants unmasks vestigial preference for ubiquitin within the NEDD8 E2. Nature Structural Mol Biol. 15, 280-7, 2008

Huang DT, Hunt HW, Zhuang M, Ohi MD, Holton JM, Schulman BA. Basis for a ubiquitin-like protein thioester switch toggling E1–E2 affinity. Nature 445, 394-8, 2007

Huang DT, Schulman BA. Breaking up with a kinky SUMO. Nature Structural Mol Biol. 13, 1045-7, 2006