MALT1 Small Molecule Inhibitors Specifically Suppress ABC-DLBCL In Vitro and In Vivo. 

Fontan L*, Yang C*, Kabaleeswaran V, Volpon L, Osborne MJ, Beltran E, Garcia M, Cerchietti L, Shaknovich R, Yang SN, Fang F, Gascoyne RD, Martinez-Climent JA, Glickman JF, Borden K, Wu H†, Melnick A†. Cancer Cell (2012). PDF

MALT1 cleavage activity is linked to the pathogenesis of activated B cell-like diffuse large B cell lymphoma
(ABC-DLBCL), a chemoresistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors. A selected lead compound, MI-2, featured direct binding to MALT1... Read More

Cyclic di-GMP Sensing via the Innate Immune Signaling Protein STING

Yin Q†, Tian Y, Kabaleeswaran V, Jiang X, Tu D, Eck MJ, Chen ZJ, Wu H†. Mol Cell (2012). PDF

Detection of foreign materials is the first step of successful immune responses. Stimulator of interferon genes (STING) was shown to directly bind cyclic diguanylate monophosphate (c-di-GMP), a bacterial second messenger, and to elicit strong interferon responses. Here we elucidate the structural features of the cytosolic c-di-GMP binding domain (CBD) of STING and its complex with c-diGMP. The CBD exhibits an a + b fold and is a dimer in the crystal and in solution. Read More

The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex
Required for Programmed Necrosis

Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H†. Cell (2012). PDF

RIP1 and RIP3 kinases are central players in TNF-induced programmed necrosis. Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. The fibrils exhibit classical characteristics of b-amyloids, as shown by... Read More

Crystal structure of inhibitor of κB kinase beta

Xu G*, Lo YC*, Li Q, Napolitano G, Wu X, Jiang X, Dreano M, Karin M, Wu H†. Nature (2011). PDF

Inhibitor of κB (IkB) kinase (IKK) phosphorylates IkB proteins, leading to their degradation and the liberation of nuclear factor kB for gene transcription. Here we report the crystal structure of IKKb in complex with an inhibitor, at a resolution of 3.6 A˚. The structure reveals a trimodular architecture comprising the kinase domain, a ubiquitin-like domain (ULD) and an elongated, a-helical scaffold/dimerization domain (SDD). Unexpectedly, the predicted leucine zipper and helix– loop–helix motifs... Read More

The Fas–FADD death domain complex structure reveals the basis of DISC assembly and disease mutations

Wang L*, Yang J*, Kabaleeswaran V*, Rice A, Cruz A, Park A, Yin Q, Damko E, Jang S, Raunser S, Robinson C, Siegel R, Walz T, Wu H†. Nature Struct Mol Biol (2010). PDF

The death-inducing signaling complex (DISC) formed by the death receptor Fas, the adaptor protein FADD and caspase-8 mediates the extrinsic apoptotic program. Mutations in Fas that disrupt the DISC cause autoimmune lymphoproliferative syndrome (ALPS). Here we show that the Fas–FADD death domain (DD)... Read More

Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling

Lin SC, Lo YC, Wu H†. Nature (2010). PDF

MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88–IRAK4–IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88–IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Read More

Crystal Structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 Complexes:
Affinity, Specificity, and Regulation

Zheng C, Kabaleeswaran V*, Wang Y*, Cheng G, Wu H†. Mol Cell (2010). PDF

TRAF1/2 and cIAP1/2 are members of the TNF receptor-associated factor (TRAF) and the inhibitor of apoptosis (IAP) families, respectively. They are critical for canonical and noncanonical NF-kB signaling pathways. Here, we report the crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes. A TRAF2 trimer interacts with one cIAP2 both in the crystal and in solution. Read More

E2 interaction and dimerization in the crystal structure of TRAF6

Yin Q, Lin SC, Lamothe B, Lu M, Lo YC, Hura G, Zheng L, Rich R, Campos A, Myszka D, Lenardo M, Darnay B, Wu H†. Nature Struct Mol Biol (2009). PDF

Tumor necrosis factor (TNF) receptor–associated factor (TRAF)-6 mediates Lys63-linked polyubiquitination for NF-jB activation via its N-terminal RING and zinc finger domains. Here we report the crystal structures of TRAF6 and its complex with the ubiquitin-conjugating enzyme (E2) Ubc13. The RING and zinc fingers of TRAF6 assume a rigid, elongated structure. Interaction of TRAF6 with Ubc13 involves direct contacts of the RING... Read More 

Structural Basis for Recognition of Diubiquitins by NEMO

Lo YC, Lin SC, Rospigliosi C, Conze D, Wu CJ, Ashwell J, Eliezer D, Wu H†. Cell (2009). PDF

NEMO is the regulatory subunit of the IkB kinase (IKK) in NF-kB activation, and its CC2-LZ region interacts with Lys63 (K63)-linked polyubiquitin to recruit IKK to receptor signaling complexes. In vitro, CC2-LZ also interacts with tandem diubiquitin. Here we report the crystal structure of CC2-LZ with two dimeric coiled coils representing CC2 and LZ, respectively. Surprisingly, mutagenesis and nuclear magnetic resonance experiments reveal that the binding sites for diubiquitins at LZ are composites... Read More