1998-2011 Publications

Highlights
* = co-first author, † = corresponding author
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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

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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

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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

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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

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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 

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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

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XIAP induces NF-κB activation via the BIR1/TAB1 interaction and BIR1 dimerization.

Lu M, Lin SC, Huang Y, Kang Y, Rich R, Lo YC, Myszka D, Han J, Wu H. Mol Cell (2007). PDF

In addition to caspase inhibition, X-linked inhibitor of apoptosis (XIAP) induces NF-κB and MAP kinase activation during TGF-b and BMP receptor signaling and upon overexpression. Here we show that the BIR1 domain of XIAP, which has no previously ascribed function, directly interacts with TAB1 to induce NF-kappaB activation. TAB1 is an upstream adaptor for the activation of the kinase TAK1... Read More

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Death Domain Assembly Mechanism Revealed by Crystal Structure of the Oligomeric PIDDosome Core Complex

Park H, Logette E, Rauser S, Cuenin S, Walz T, Tschopp J, Wu H. Cell (2007). PDF

Proteins of the death domain (DD) superfamily mediate assembly of oligomeric signaling complexes for the activation of caspases and kinases via unknown mechanisms. Here we report the crystal structure of the PIDD DD and RAIDD DD complex, which forms the core of the caspase-2-activating complex PIDDosome. Although RAIDD DD and PIDD DD are monomers, they assemble into a complex that comprises seven... Read More

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Caspase-9 Holoenzyme Is a Specific and Optimal Procaspase-3 Processing Machine.

Yin Q, Park H, Chung J, Lin SC, Lo YC, Graca L, Jiang X, Wu H. Mol Cell (2006). PDF

Caspase-9 activation is critical for intrinsic cell death. The activity of caspase-9 is increased dramatically
upon association with the apoptosome, and the apoptosome bound caspase-9 is the caspase-9 holoenzyme
(C9Holo). In this study, we use quantitative enzymatic assays to fully characterize C9Holo and a leucine-zipper-linked dimeric caspase-9 (LZ-C9). We surprisingly show that LZ-C9 is... Read More

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Crystal Structure of MC159 Reveals Molecular Mechanism of DISC Assembly and FLIP Inhibition

Yang J K*, Wang L*, Zheng L, Wan F, Ahmed M, Lenardo M, Wu HMol Cell (2005). PDF

Death receptors (DRs) in the Tumor Necrosis Factor (TNF) Receptor (TNFR) superfamily mediate the extrinsic pathway of apoptosis and play critical roles in embryonic development, cellular homeostasis, and immune regulation (French and Tschopp, 2003; Locksley et al., 2001; Peter and Krammer, 2003; Wajant, 2002). Current members of the DR subfamily include Fas (also known as CD95 and APO-1), TNF-R1... Read More

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Bicarbonate activation of adenylyl cyclases via promotion of the catalytic cycle: active site closure and metal recruitment

Steegborn C, Litvin T N, Levin L R, Buck J, Wu H. Nature Struct. & Mol. Biol. (2005). PDF | Commentary

The ubiquitous second messenger cAMP regulates a large variety of essential physiological processes such as gene expression, chromosome segregation and cellular metabolism. In mammalian cells, cAMP is synthesized by a family of nine transmembrane adenylyl cyclases (tmACs) and one sAC1. Unlike tmACs, which localize to the cellular membrane and respond to extracellular stimuli via... Read More

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ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer’s Disease

Lustbader J*, Cirilli M*, Lin C*, Xu H W, Caspersen C, Wang N, Takuma K, Chen X, Chaney M, Trinchese F, Liu S,
Kuppusamy P, Zewier Z, Arancio O, Stern D, Yan S D*†, Wu H*†. Science (2004). PDF

Mitochondrial dysfunction is a hallmark of β-amyloid (Aβ)–induced neuronal toxicity in Alzheimer’s disease (AD). Here, we demonstrate that Aβ-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Aβ to mitochondrial toxicity. Aβ interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Aβ-bound ABAD shows substantial deformation of the active site that... Read More

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Distinct molecular mechanism for initiating TRAF6 signalling

Ye H*, Arron J*, Lamothe B, Cirilli M, Kobayashi T, Shvede N, Segal D, Dzivenu O, Vologodskaia M*, Yim M, Du K, Singh S, Pike J W, Darnay B, Choi Y, Wu H†. Nature (2002). PDF 

Tumour-necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is the only TRAF family member that participates in signal transduction of both the TNF receptor (TNFR) superfamily and the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily1–5; it is important for adaptive immunity, innate immunity and bone homeostasis. Here we report crystal structures of TRAF6, alone and in complex with... Read More

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Structural Basis of Caspase Inhibition by XIAP: Differential Roles of the Linker versus the BIR Domain

Huang Y*, Park Y C*, Rich R L, Segal D, Myszka D G, Wu H†. Cell (2001). PDF 

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Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex

Xu G, Cirilli M, Huang Y, Rich R L, Myszka D G, Wu H†. Nature (2001). PDF

Apoptosis is a highly regulated process that is crucial for normal development and homeostasis of multicellular organisms. The p35 protein from baculoviruses effectively prevents apoptosis by its broad-spectrum caspase inhibition. Here we report the crystal structure of p35 in complex with human caspase-8 at 3.0 Å resolution and biochemical and mutagenesis studies based on the structural information... Read More

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Ye H, Cande C, Stephanou N, Gurgusani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H†. Nature Structural Biology (2002). PDF 

The execution of apoptosis or programmed cell death comprises both caspase-dependent and caspase-independent processes. Apoptosis inducing factor (AIF) was identified as a major player in caspase-independent cell death. It induces chromatin condensation and initial DNA cleavage via an unknown molecular mechanism. Here we report the crystal structure of human AIF at 1.8 Å resolution... Read More

DNA binding is required for the apoptogenic action of apoptosis inducing factor

The inhibitor of apoptosis proteins (IAPs) represent the only endogenous cascade inhibitors and are characterized by the presence of baculoviral IAP repeats (BIRs). Here, we report the crystal structure of the complex between human caspase-7 and XIAP (BIR2 and the proceeding linker). The structure surprisingly reveals that the linker is the only contacting element for the caspase, while the  Read More

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A Novel Mechanism of TRAF Signaling Revealed by Structural and Functional Analyses of the TRADD–TRAF2 Interaction

Park Y C, Ye H, Hsia C, Segal D, Rich R L, Liou H C, Myszka D G, Wu H†. Cell (2000). PDF

TRAF proteins are major mediators for the cell activation, cell survival, and antiapoptotic functions of the TNF receptor superfamily. They can be recruited to activated TNF receptors either by direct interactions with the receptors or indirectly via the adaptor protein TRADD. We now report the structure... Read More

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The structural basis for the recognition of diverse receptor sequences by TRAF2.

Ye H, Park Y C, Kreishman M, Kieff E, Wu H†. Mol Cell (1999). PDF

Many members of the tumor necrosis factor receptor (TNFR) superfamily initiate intracellular signaling by recruiting TNFR-associated factors (TRAFs) through their cytoplasmic tails. TRAFs apparently recognize highly diverse receptor sequences. Crystal structures of the TRAF domain of human TRAF2 in complex with peptides from the TNFR family members CD40, CD30, Ox40, 4-1BB,.. Read More

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Structural basis for self-association and receptor recognition of human TRAF2

Park Y C, Burkitt V, Villa A R, Tong L, Wu H†. Nature (1999). PDF

Tumour necrosis factor (TNF)-receptor-associated factors (TRAFs) form a family of cytoplasmic adapter proteins that mediate signal transduction from many members of the TNF-receptor superfamily and the interleukin-1 receptor1 . They are important in the regulation of cell survival and cell death. The carboxy-terminal region of TRAFs (the TRAF domain) is required for self-association and interaction with receptors... Read More

Other Publications (1998-2011)
* = co-first author, † = corresponding author

Wu H*, Siegel RM*. Medicine. (2011). Progranulin resolves inflammation. Science. 332:427-8

Zheng C*, Yin Q*, Wu H†. (2011). Structural studies of NF-kB signaling. Cell Research. 21:183-959

H Wu, YC Lo, Q Yin. (2011). Structural studies of NEMO and TRAF6: implications in NF-kB activation. Adv Exp Med Biol. 691: 89-91

Wu H†, Lo YC, Lin SC. (2010). Recent advances in polyubiquitin chain recognition. F1000 Biol Reports. 2:1-5

Zheng C, Wu H†. (2010). RIG-I "sees" the 5'-triphosphate. Structure.18:894-6

Yin Q, Lamothe B, Darnay B, Wu H†. (2009). Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry. 48:10558-67

Pan W*, da Graca LS*, Shao Y, Yin Q, Wu H, Jiang X†. (2009). PHAPI/pp32 suppresses tumorigenesis by stimulating apoptosis. J Biol Chem. 284:6946-6954

Yin Q, Lin SC, Lo YC, Damo S, Wu H. (2009). Tumor Necrosis Factor Receptor- Associated Factors in Immune Receptor Signal Transduction. Handbook of Cell Signaling, edited by Bradshaw. Pages 339-345

Wu H*, Hymowitz S*. (2009). Structure and Function of Tumor Necrosis Factor (TNF) at the Cell Surface. Handbook of Cell Signaling, edited by Bradshaw. Pages 265-275

Wu H*, Lo YC*. (2009). Structures, domains and functions in cell death (DD, DED, CARD, PYD). In Encyclopedia of Life Sciences. John Wiley & Sons Ltd, Chichester

Lin SC*, Chung JY*, Lamothe B, Rajashankar K, Lu M, Lo YC, Lam AY, Darnay BG, Wu H. (2008). Molecular Basis for the Unique Deubiquitinating Activity of the NF-kappaB Inhibitor A20. J Mol Biol. 376:526-40. Commentary

Lo YC*, Maddineni U*, Chung JY, Rich RL, Myszka DG, Wu H†. (2008). High-affinity interaction between IKKbeta and NEMO. Biochemistry. 47:3109-16

Wu H, Tschopp J, Lin SC. (2007). Smac mimetics and TNFalpha: a dangerous liaison? Cell. 131:655-65

Lin SC, Huang Y, Lo YC, Lu M, Wu H. (2007). Crystal Structure of the BIR1 Domain of XIAP in Two Crystal Forms. J Mol Biol. 372:847-854

Gao Z, Tian Y, Wang J, Yin Q, Wu H, Li YM, Jiang X. (2007). A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP: Dynamic and cooperative regulation of XIAP by Smac/Diablo. J Biol Chem. 282:30718-27

Park H, Wu, H. (2007). Crystallization and preliminary X-ray crystallographic studies of the oligomeric death domain complex between PIDD and RAIDD. Acta Crystallogr. F63:229-32

Besse A, Lamothe B, Campos A, Webster W, Maddineni U, Lin SC, Wu, H, Darnay B. (2007). TAK1-dependent signaling requires functional interaction with TAB2/TAB3. J Biol Chem. 282:3918-28

Lamothe B, Besse A, Campos AD, Webster WK, Wu H and Darnay BG. (2007). Site-specific Lys63-linked TRAF6 auto-ubiquitination is a critical determinant of IKK activation. J Biol Chem. 282:4102-12

Yan S, Chen X, Wu H. (2007). ABAD: Mitochondrial Target for A!-Mediated Cellular Perturbation in Alzheimer Disease. in Research Progress in Alzheimer's Disease and Dementia, Vol. 3, edited by Miao-Kun Sun. pages 175-189

Park H, Lo YC, Lin SC, Wang L, Yang J, Wu H. (2007). The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation. Ann Rev Immunol. 25:561-86

Lu M, Min T, Eliezer D, Wu H. (2006). A novel role for native chemical ligation in covalent caspase inhibition by p35Chemistry and Biology. 13: 117-22. Commentary

Park H H, Tookes H E, Wu H. (2006). Crystallization and preliminary X-ray crystallographic studies of Drep-3, a DFF-related protein from Drosophila melanogaster. Acta Crystallogr. F62:597-599

Muppidi J, Lobito A, Yang J K, Wang L, Wu H, Siegel R. (2006). Homotypic FADD interactions though a conserved RXDLL motif are required for death receptor-induced apoptosisCell death and differentiation. 13:1641-50

Guasparri I, Wu H, Cesarman E. (2006). The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signaling. EMBO Rep. 7:114-9

Park H H, Wu H. (2006). Crystal Structure of RAIDD Death Domain Implicates Potential Mechanism of PIDDosome Assembly. J Mol Biol. 357:358-64

Chung J, Lu M, Yin Q, Lin SC, Wu H. (2006). Molecular basis for the unique specificity of TRAF6. In TNF Receptor Associated Factors, edited by Hao Wu, Pages 122-130

Chung J, Lu M, Yin Q, Wu H. (2006). Structural revelation of TRAF2 function. In TNF Receptor Associated Factors, edited by Hao Wu. Pages 93-113

Steegborn C*, Litvin TN*, Hess KC, Capper AB, Taussig R, Buck J, Levin LR, Wu H (2005). A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen. J Biol Chem. 280:31754-93

Huang Y, Lu M, Wu H. (2004). XIAP inhibitors for cancer treatment: removing the brakes of apoptosis? Cancer Cell. 5:1-2

Ye H, Chen T, Xu X, Pennycooke M, Wu H, Steegborn C. (2004). Crystal structure of the putative adapter protein MTH1859. J Struct Biol. 148:251-6

Dzivenu O K, Park H H, Wu H. (2004). General co-expression vectors for the overexpression of heterodimeric protein complexes in Escherichia coli. Protein Expr Purif. 38: 1-8

Huang Y, Lu M, Wu H. (2004). Antagonizing XIAP-mediated caspase-3 inhibition. Achilles' heel of cancers? Cancer Cell. 5:1-2

Wu H*. (2004). Assembly of post-receptor signaling complexes for the TNF receptor superfamily. Advances in Protein Chemistry. 68:225-79

Park H H, Wu H. (2004). Gauging length: recognition of small interfering RNAs. Structure. 12:172-173

Moldovan MC*, Yachou A*, Levesque K, Wu H, Hendrickson WA, Cohen EA, Sekaly RP. (2002). CD4 dimers constitute the functional component required for T cell activation. J. Immunology. 169:6261-8

Xu G, Rich R L, Steegborn C, Min T, Huang Y, Myszka D G, Wu H. (2003). Mutational Analyses of the p35/caspase Interaction: A bowstring kinetic model of caspase inhibition by P35. J Biol Chem. 278:5455-61

Huang Y, Rich R, Myszka D, Wu H. (2003). Requirement of both the BIR2 and BIR3 domains for the relief of XIAP-mediated caspase inhibition by Smac

J Biol Chem. 278:49517-22

Chung J, Park Y C, Ye H, Wu H. (2003). TNF receptor associated factors. In Handbook of Cell Signaling. 1:311

Wu H†, Arron J. (2003). TRAF6, a molecular bridge of adaptive immunity, innate immunity and bone homeostasis. Bioessays. 25:1096-1105

Ye H, Cirilli M, Wu H. (2002). The use of construct variation and diffraction data analysis in the crystallization of the TRAF domain of human tumor necrosis factor receptor associated factor 6. Acta Crystallogr D Biol Crystallogr. 58:1886-1888

Chung J, Park Y C, Ye H, Wu H. (2002). All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci. 115:679-688

e H, Wu H. (2000). Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry. Proc Natl Acad Sci U S A. 97:8961-6

Ni C Z, Welsh K, Leo E, Chiou C K, Wu H, Reed J C, Ely K R. (2000). Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci U S A. 97:10395-9

Wu H, Park Y C, Ye H, Tong L. (1999). Structural studies of human TRAF2. in Cold Spring Harbor Symposium Quant Biol (Signaling and Gene Expression in the Immune System). 64:541-549

Bhargava G, Mui S, Pav S, Wu H, Loeber G, Tong L. (1999). Preliminary crystallographic studies of human mitochondrial NAD(P)(+)- dependent malic enzyme. J Struct Biol. 127:72-5

Xu Y, Bhargava G, Wu H, Loeber G, Tong L. (1999). Crystal structure of human mitochondrial NAD(P)+-dependent malic enzyme: a new class of oxidative decarboxylases. Structure. 41:6928-38

Lustbader J W, Lobel L, Wu H, Elliott M M. (1998). Structural and molecular studies of human chorionic gonadotropin and its receptor. Recent Prog Horm. 53:395-424