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Wang, Jia-Huai

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Wang

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Jia-Huai

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Wang, Jia-Huai

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2011 - 201811

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Author's Publications: search.filters.isAuthorOfPublication.24c5e4f7-2087-43e4-a9fb-479b28782996

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Now showing 1 - 10 of 11
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    Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination
    (Frontiers Media S.A., 2015) Brazin, Kristine; Mallis, Robert; Das, Dibyendu Kumar; Feng, Yinnian; Hwang, Wonmuk; Wang, Jia-Huai; Wagner, Gerhard; Lang, Matthew J.; Reinherz, Ellis
    The αβTCR was recently revealed to function as a mechanoreceptor. That is, it leverages mechanical energy generated during immune surveillance and at the immunological synapse to drive biochemical signaling following ligation by a specific foreign peptide–MHC complex (pMHC). Here, we review the structural features that optimize this transmembrane (TM) receptor for mechanotransduction. Specialized adaptations include (1) the CβFG loop region positioned between Vβ and Cβ domains that allosterically gates both dynamic T cell receptor (TCR)–pMHC bond formation and lifetime; (2) the rigid super β-sheet amalgams of heterodimeric CD3εγ and CD3εδ ectodomain components of the αβTCR complex; (3) the αβTCR subunit connecting peptides linking the extracellular and TM segments, particularly the oxidized CxxC motif in each CD3 heterodimeric subunit that facilitates force transfer through the TM segments and surrounding lipid, impacting cytoplasmic tail conformation; and (4) quaternary changes in the αβTCR complex that accompany pMHC ligation under load. How bioforces foster specific αβTCR-based pMHC discrimination and why dynamic bond formation is a primary basis for kinetic proofreading are discussed. We suggest that the details of the molecular rearrangements of individual αβTCR subunit components can be analyzed utilizing a combination of structural biology, single-molecule FRET, optical tweezers, and nanobiology, guided by insightful atomistic molecular dynamic studies. Finally, we review very recent data showing that the pre-TCR complex employs a similar mechanobiology to that of the αβTCR to interact with self-pMHC ligands, impacting early thymic repertoire selection prior to the CD4+CD8+ double positive thymocyte stage of development.
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    Structure of unliganded membrane-proximal domains FN4-FN5-FN6 of DCC
    (Higher Education Press, 2017) Finci, Lorenzo I.; Zhang, Jie; Sun, Xiaqin; Smock, Robert G.; Meijers, Rob; Zhang, Yan; Xiao, Junyu; Wang, Jia-Huai
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    The binding of DCC-P3 motif and FAK-FAT domain mediates the initial step of netrin-1/DCC signaling for axon attraction
    (Nature Publishing Group UK, 2018) Xu, Shutong; Liu, Yiqiong; Li, Xiaolong; Liu, Ying; Meijers, Rob; Zhang, Yan; Wang, Jia-Huai
    Netrin-1 plays a key role in axon guidance through binding to its receptor, Deleted in Colorectal Cancer (DCC). The initial step of signaling inside the cell after netrin-1/DCC ligation is the binding of DCC cytoplasmic P3 motif to focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). Here we report the crystal structure of P3/FAT complex. The helical P3 peptide interacts with a helix-swapped FAT dimer in a 2:2 ratio. Dimeric FAT binding is P3-specific and stabilized by a calcium ion. Biochemical studies showed that DCC-P3 motif and calcium ion could facilitate FAT dimerization in solution. Axon guidance assays confirm that the DCC/FAK complex is essential for netrin-1-induced chemoattraction. We propose that netrin-1/DCC engagement creates a small cluster of P3/FAT for FAK recruitment close to the cell membrane, which exerts a concerted effect with PIP2 for FAK signaling. We also compare P3/FAT binding with paxillin/FAT binding and discuss their distinct recognition specificity on a common FAT domain for axon attraction versus integrin signaling, respectively.
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    Strict Major Histocompatibility Complex Molecule Class-Specific Binding by Co-Receptors Enforces MHC-Restricted αβ TCR Recognition during T Lineage Subset Commitment
    (Frontiers Media S.A., 2013) Li, Xiao-Long; Teng, Mai-Kun; Reinherz, Ellis; Wang, Jia-Huai
    Since the discovery of co-receptor dependent αβTCR recognition, considerable effort has been spent on elucidating the basis of CD4 and CD8 lineage commitment in the thymus. The latter is responsible for generating mature CD4 helper and CD8αβ cytotoxic T cell subsets. Although CD4+ and CD8+ T cell recognition of peptide antigens is known to be MHC class II- and MHC class I-restricted, respectively, the mechanism of single positive (SP) thymocyte lineage commitment from bipotential double-positive (DP) progenitors is not fully elucidated. Classical models to explain thymic CD4 vs. CD8 fate determination have included a stochastic selection model or instructional models. The latter are based either on strength of signal or duration of signal impacting fate. More recently, differential co-receptor gene imprinting has been shown to be involved in expression of transcription factors impacting cytotoxic T cell development. Here, we address commitment from a structural perspective, focusing on the nature of co-receptor binding to MHC molecules. By surveying 58 MHC class II and 224 MHC class I crystal structures in the Protein Data Bank, it becomes clear that CD4 cannot bind to MHC I molecules, nor can CD8αβ or CD8αα bind to MHC II molecules. Given that the co-receptor delivers Lck to phosphorylate exposed CD3 ITAMs within a peptide/MHC (pMHC)-ligated TCR complex to initiate cell signaling, this strict co-receptor recognition fosters MHC class-restricted SP thymocyte lineage commitment at the DP stage even though both co-receptors are expressed on a single cell. In short, the binding preference of an αβTCR for a peptide complexed with an MHC molecule dictates which co-receptor subsequently binds, thereby supporting development of that subset lineage. How function within the lineage is linked further to biopotential fate determination is discussed.
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    Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding
    (eLife Sciences Publications, Ltd, 2014) Gelfand, Maria V; Hagan, Nellwyn; Tata, Aleksandra; Oh, Won-Jong; Lacoste, Baptiste; Kang, Kyu-Tae; Kopycinska, Justyna; Bischoff, Joyce; Wang, Jia-Huai; Gu, Chenghua
    During development, tissue repair, and tumor growth, most blood vessel networks are generated through angiogenesis. Vascular endothelial growth factor (VEGF) is a key regulator of this process and currently both VEGF and its receptors, VEGFR1, VEGFR2, and Neuropilin1 (NRP1), are targeted in therapeutic strategies for vascular disease and cancer. NRP1 is essential for vascular morphogenesis, but how NRP1 functions to guide vascular development has not been completely elucidated. In this study, we generated a mouse line harboring a point mutation in the endogenous Nrp1 locus that selectively abolishes VEGF-NRP1 binding (Nrp1VEGF−). Nrp1VEGF− mutants survive to adulthood with normal vasculature revealing that NRP1 functions independent of VEGF-NRP1 binding during developmental angiogenesis. Moreover, we found that Nrp1-deficient vessels have reduced VEGFR2 surface expression in vivo demonstrating that NRP1 regulates its co-receptor, VEGFR2. Given the resources invested in NRP1-targeted anti-angiogenesis therapies, our results will be integral for developing strategies to re-build vasculature in disease. DOI: http://dx.doi.org/10.7554/eLife.03720.001
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    The immunology connection—my first T cell receptor structure projects
    (Higher Education Press, 2014) Wang, Jia-Huai
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    Crystal structure of HLA-B*5801, a protective HLA allele for HIV-1 infection
    (Higher Education Press, 2016) Li, Xiaolong; Lamothe, Pedro A.; Ng, Robert; Xu, Shutong; Teng, Maikun; Walker, Bruce; Wang, Jia-Huai
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    Protein production, crystallization and preliminary crystallographic analysis of the four N-terminal immunoglobulin domains of Down syndrome cell adhesion molecule 1. Corrigendum
    (International Union of Crystallography, 2016) Cheng, Linna; Li, Shu-Ang; Wang, Jia-Huai; Yu, Yamei; Chen, Qiang
    An extra author is added to the article by Chen et al. [(2015), Acta Cryst. F71, 775–778].
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    A Conserved Hydrophobic Patch on V\(\beta\) Domains Revealed by TCR\(\beta\) Chain Crystal Structures: Implications for Pre-TCR Dimerization
    (Frontiers Research Foundation, 2011) Zhou, Bo; Chen, Qian; Mallis, Robert; Zhang, Hongmin; Liu, Jin-Huan; Reinherz, Ellis; Wang, Jia-Huai
    The \(\alpha\beta\) T cell receptor (TCR) is a multimeric complex whose \(\beta\) chain plays a crucial role in thymocyte development as well as antigen recognition by mature T lymphocytes. We report here crystal structures of individual \(\beta\) subunits, termed N15\(\beta\) (V\(\beta\)5.2D\(\beta\)2J\(\beta\)2.6C\(\beta\)2) and N30\(\beta\) (V\(\beta\)13D\(\beta\)1J\(\beta\)1.1C\(\beta\)2), derived from two \(\alpha\beta\) TCRs specific for the immunodominant vesicular stomatitis virus octapeptide (VSV-8) bound to the murine H-2K\(^b\) MHC class I molecule. The crystal packing of the N15\(\beta\) structure reveals a homodimer formed through two V\(\beta\) domains. The V\(\beta\)/V\(\beta\) module is topologically very similar to the V\(\alpha\)/V\(\beta\) module in the N15\(\alpha\beta\) heterodimer. By contrast, in the N30\(\beta\) structure, the V\(\beta\) domain’s external hydrophobic CFG face is covered by the neighboring molecule’s C\(\beta\) domain. In conjunction with systematic investigation of previously published TCR single-subunit structures, we identified several conserved residues forming a concave hydrophobic patch at the center of the CFG outer face of the V\(\beta\) and other V-type Ig-like domains. This hydrophobic patch is shielded from solvent exposure in the crystal packing, implying that it is unlikely to be thermodynamically stable if exposed on the thymocyte surface. Accordingly, we propose a dimeric pre-TCR model distinct from those suggested previously by others and discuss its functional and structural implications.
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    Revisiting the putative TCR Cα dimerization model through structural analysis
    (Frontiers Media S.A., 2013) Wang, Jia-Huai; Reinherz, Ellis
    Despite major advances in T cell receptor (TCR) biology and structure, how peptide–MHC complex (pMHC) ligands trigger αβ TCR activation remains unresolved. Two views exist. One model postulates that monomeric TCR–pMHC ligation events are sufficient while a second proposes that TCR–TCR dimerization in cis via Cα domain interaction plus pMHC binding is critical. We scrutinized 22 known TCR/pMHC complex crystal structures, and did not find any predicted molecular Cα–Cα contacts in these crystals that would allow for physiological TCR dimerization. Moreover, the presence of conserved glycan adducts on the outer face of the Cα domain preclude the hypothesized TCR dimerization through the Cα domain. Observed functional consequences of Cα mutations are likely indirect, with TCR microclusters at the immunological synapse driven by TCR transmembrane/cytoplasmic interactions via signaling molecules, scaffold proteins, and/or cytoskeletal elements.