Scholars@Duke
Kunhong Xiao

Kunhong Xiao

Adjunct Assistant Professor in the Department of Medicine
Medicine, Cardiology
khxiao@receptor-biol.duke.edu
Box 3126 Med Ctr, Durham, NC 27710
E1355 Thomas E. Starzl Biomedi, Pittsburgh, PA 15261

Selected Publications

S-nitrosylation is required for β2AR desensitization and experimental asthma.

Journal Article Mol Cell · August 18, 2022 The β2-adrenergic receptor (β2AR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of β-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation ... Full text Link to item Cite

Structural studies of phosphorylation-dependent interactions between the V2R receptor and arrestin-2.

Journal Article Nat Commun · April 22, 2021 Arrestins recognize different receptor phosphorylation patterns and convert this information to selective arrestin functions to expand the functional diversity of the G protein-coupled receptor (GPCR) superfamilies. However, the principles governing arrest ... Full text Link to item Cite

DeSiphering receptor core-induced and ligand-dependent conformational changes in arrestin via genetic encoded trimethylsilyl 1H-NMR probe.

Journal Article Nat Commun · September 25, 2020 Characterization of the dynamic conformational changes in membrane protein signaling complexes by nuclear magnetic resonance (NMR) spectroscopy remains challenging. Here we report the site-specific incorporation of 4-trimethylsilyl phenylalanine (TMSiPhe) ... Full text Link to item Cite

βarrestin-1 regulates DNA repair by acting as an E3-ubiquitin ligase adaptor for 53BP1.

Journal Article Cell Death Differ · April 2020 Cellular DNA is constantly under threat from internal and external insults, consequently multiple pathways have evolved to maintain chromosomal fidelity. Our previous studies revealed that chronic stress, mediated by continuous stimulation of the β2-adrene ... Full text Link to item Cite

Site-specific polyubiquitination differentially regulates parathyroid hormone receptor-initiated MAPK signaling and cell proliferation.

Journal Article J Biol Chem · April 13, 2018 G protein-coupled receptor (GPCR) signaling and trafficking are essential for cellular function and regulated by phosphorylation, β-arrestin, and ubiquitination. The GPCR parathyroid hormone receptor (PTHR) exhibits time-dependent reversible ubiquitination ... Full text Link to item Cite

Elucidating structural and molecular mechanisms of β-arrestin-biased agonism at GPCRs via MS-based proteomics.

Journal Article Cell Signal · January 2018 The discovery of β-arrestin-dependent GPCR signaling has led to an exciting new field in GPCR pharmacology: to develop "biased agonists" that can selectively target a specific downstream signaling pathway that elicits beneficial therapeutic effects without ... Full text Link to item Cite

Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling.

Journal Article Nat Commun · February 9, 2017 Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signa ... Full text Link to item Cite

Phosphorylation of Src by phosphoinositide 3-kinase regulates beta-adrenergic receptor-mediated EGFR transactivation.

Journal Article Cell Signal · October 2016 β2-Adrenergic receptors (β2AR) transactivate epidermal growth factor receptors (EGFR) through formation of a β2AR-EGFR complex that requires activation of Src to mediate signaling. Here, we show that both lipid and protein kinase activities of the bifuncti ... Full text Link to item Cite

Discovery of novel FFA4 (GPR120) receptor agonists with β-arrestin2-biased characteristics.

Journal Article Future Med Chem · 2015 BACKGROUND: Free fatty acid 4 (FFA4) (GPR120) receptor functions as a receptor for unsaturated long-chain free fatty acids by regulating the secretion of glucagon-like peptide-1 and suppressing the inflammatory process, in which these two distinct biologic ... Full text Link to item Cite

The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes.

Journal Article Cell Res · September 2014 The tyrosine phosphorylation barcode encoded in C-terminus of HER2 and its ubiquitination regulate diverse HER2 functions. PTPN18 was reported as a HER2 phosphatase; however, the exact mechanism by which it defines HER2 signaling is not fully understood. H ... Full text Link to item Cite

Visualization of arrestin recruitment by a G-protein-coupled receptor.

Journal Article Nature · August 14, 2014 G-protein-coupled receptors (GPCRs) are critically regulated by β-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling. A recent surge of structural data on a number of GPCRs, including the ... Full text Open Access Link to item Cite

Copper is required for oncogenic BRAF signalling and tumorigenesis.

Journal Article Nature · May 22, 2014 The BRAF kinase is mutated, typically Val 600→Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAF(V600E) phosphorylates a ... Full text Link to item Cite

Recent developments in biased agonism.

Journal Article Curr Opin Cell Biol · April 2014 The classic paradigm of G protein-coupled receptor (GPCR) activation was based on the understanding that agonist binding to a receptor induces or stabilizes a conformational change to an 'active' conformation. In the past decade, however, it has been appre ... Full text Link to item Cite

Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase.

Journal Article J Neurochem · January 2014 Striatal-enriched tyrosine phosphatase (STEP) is an important regulator of neuronal synaptic plasticity, and its abnormal level or activity contributes to cognitive disorders. One crucial downstream effector and direct substrate of STEP is extracellular si ... Full text Link to item Cite

The posterior cricoarytenoid muscle is spared from MuRF1-mediated muscle atrophy in mice with acute lung injury.

Journal Article PLoS One · 2014 BACKGROUND: Skeletal muscle wasting in acute lung injury (ALI) patients increases the morbidity and mortality associated with this critical illness. The contribution of laryngeal muscle wasting to these outcomes is unknown, though voice impairments and asp ... Full text Link to item Cite

Monitoring protein conformational changes and dynamics using stable-isotope labeling and mass spectrometry.

Journal Article Nat Protoc · 2014 An understanding of the mechanism accompanying functional conformational changes associated with protein activation has important implications for drug design. Here we describe a powerful method, conformational changes and dynamics using stable-isotope lab ... Full text Link to item Cite

Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide.

Journal Article Nature · May 2, 2013 The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second ... Full text Link to item Cite

Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunction.

Journal Article J Mol Cell Cardiol · January 2013 Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase whose biological function remains largely unknown. We have recently shown that TNNI3K expression greatly accelerates cardiac dysfunction in mouse models of cardiomyopathy, indicati ... Full text Link to item Cite

Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide

Journal Article Nature · 2013 The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second ... Full text Cite

Cadmium is a potent inhibitor of PPM phosphatases and targets the M1 binding site.

Journal Article Sci Rep · 2013 The heavy metal cadmium is a non-degradable pollutant. By screening the effects of a panel of metal ions on the phosphatase activity, we unexpectedly identified cadmium as a potent inhibitor of PPM1A and PPM1G. In contrast, low micromolar concentrations of ... Full text Link to item Cite

MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors.

Journal Article J Cell Biol · November 26, 2012 Lysosomal degradation of ubiquitinated β(2)-adrenergic receptors (β(2)ARs) serves as a major mechanism of long-term desensitization in response to prolonged agonist stimulation. Surprisingly, the βAR antagonist carvedilol also induced ubiquitination and ly ... Full text Link to item Cite

Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling.

Journal Article Trends Biochem Sci · September 2011 Featured Publication β-Arrestins, originally discovered to desensitize activated seven transmembrane receptors (7TMRs; also known as G-protein-coupled receptors, GPCRs), are now well established mediators of receptor endocytosis, ubiquitylation and G protein-independent signal ... Full text Link to item Cite

A tale of two sites: How ubiquitination of a G protein-coupled receptor is coupled to its lysosomal trafficking from distinct receptor domains.

Journal Article Commun Integr Biol · September 2011 The β(2)-adrenergic receptor (β(2)AR) is a prototypical G(s)-coupled receptor belonging to the superfamily of seven transmembrane spanning heptahelical receptors (7TMRs or G protein-coupled receptors [GPCRs])-therapeutically the most diverse and accessible ... Full text Link to item Cite

Multiple ligand-specific conformations of the β2-adrenergic receptor.

Journal Article Nat Chem Biol · August 21, 2011 Featured Publication Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adap ... Full text Link to item Cite

A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1.

Journal Article Nature · August 21, 2011 Featured Publication The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is gene ... Full text Link to item Cite

Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin.

Journal Article Sci Signal · August 9, 2011 Featured Publication Phosphorylation of G protein-coupled receptors (GPCRs, which are also known as seven-transmembrane spanning receptors) by GPCR kinases (GRKs) plays essential roles in the regulation of receptor function by promoting interactions of the receptors with β-arr ... Full text Link to item Cite

Beta2-adrenergic receptor lysosomal trafficking is regulated by ubiquitination of lysyl residues in two distinct receptor domains.

Journal Article J Biol Chem · April 8, 2011 Featured Publication Agonist stimulation of the β2-adrenergic receptors (β2ARs) leads to their ubiquitination and lysosomal degradation. Inhibition of lysosomal proteases results in the stabilization and retention of internalized full-length β2ARs in the lysosomes, whereas inh ... Full text Link to item Cite

Arresting a transient receptor potential (TRP) channel: beta-arrestin 1 mediates ubiquitination and functional down-regulation of TRPV4.

Journal Article J Biol Chem · September 24, 2010 β-Arrestins, originally discovered to desensitize activated G protein-coupled receptors, (aka seven-transmembrane receptors, 7TMRs) also mediate 7TMR internalization and G protein-independent signaling via these receptors. More recently, several regulatory ... Full text Link to item Cite

Inferring the sign of kinase-substrate interactions by combining quantitative phosphoproteomics with a literature-based mammalian kinome network

Journal Article 10th IEEE International Conference on Bioinformatics and Bioengineering 2010, BIBE 2010 · September 6, 2010 Protein phosphorylation is a reversible post-translational modification commonly used by cell signaling networks to transmit information about the extracellular environment into intracellular organelles for the regulation of the activity and sorting of pro ... Full text Cite

Global phosphorylation analysis of beta-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR).

Journal Article Proc Natl Acad Sci U S A · August 24, 2010 Featured Publication beta-Arrestin-mediated signaling downstream of seven transmembrane receptors (7TMRs) is a relatively new paradigm for signaling by these receptors. We examined changes in protein phosphorylation occurring when HEK293 cells expressing the angiotensin II typ ... Full text Link to item Cite

Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL.

Journal Article Sci Signal · July 7, 2009 Featured Publication Agonist-induced ubiquitylation and degradation of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play an essential role in surface receptor homeostasis, thereby tuning many physiological processes. Although beta-arr ... Full text Link to item Cite

Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.

Journal Article Proc Natl Acad Sci U S A · April 21, 2009 Featured Publication Beta-arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-transmembrane receptors (7TMRs). Agonist-stimulated ubiquitination of beta-arrestin2 mediated by the E3 ubiquitin ligase Md ... Full text Link to item Cite

BiPS, a photocleavable, isotopically coded, fluorescent cross-linker for structural proteomics.

Journal Article Mol Cell Proteomics · February 2009 Featured Publication Cross-linking combined with mass spectrometry is an emerging approach for studying protein structure and protein-protein interactions. However, unambiguous mass spectrometric identification of cross-linked peptides derived from proteolytically digested cro ... Full text Link to item Cite

Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor.

Journal Article J Biol Chem · August 8, 2008 Featured Publication Agonist-stimulated beta(2)-adrenergic receptor (beta(2)AR) ubiquitination is a major factor that governs both lysosomal trafficking and degradation of internalized receptors, but the identity of the E3 ubiquitin ligase regulating this process was unknown. ... Full text Link to item Cite

Beta-arrestin-mediated localization of smoothened to the primary cilium.

Journal Article Science · June 27, 2008 Featured Publication beta-Arrestins have important roles in the regulation of seven-transmembrane receptors (7TMRs). Smoothened (Smo) is a 7TMR that mediates effects of Hedgehog on developmental processes and whose dysregulation may cause tumorigenesis. beta-Arrestins are requ ... Full text Link to item Cite

Ubiquitination of beta-arrestin links seven-transmembrane receptor endocytosis and ERK activation.

Journal Article J Biol Chem · October 5, 2007 Beta-arrestin2 and its ubiquitination play crucial roles in both internalization and signaling of seven-transmembrane receptors (7TMRs). To understand the connection between ubiquitination and the endocytic and signaling functions of beta-arrestin, we gene ... Full text Link to item Cite

The active conformation of beta-arrestin1: direct evidence for the phosphate sensor in the N-domain and conformational differences in the active states of beta-arrestins1 and -2.

Journal Article J Biol Chem · July 20, 2007 Featured Publication beta-Arrestins are multifunctional adaptor proteins that regulate seven transmembrane-spanning receptor (7TMR) desensitization and internalization and also initiate alternative signaling pathways. Studies have shown that beta-arrestins undergo a conformati ... Full text Link to item Cite

Functional specialization of beta-arrestin interactions revealed by proteomic analysis.

Journal Article Proc Natl Acad Sci U S A · July 17, 2007 Featured Publication Beta-arrestins are cytosolic proteins that form complexes with seven-transmembrane receptors after agonist stimulation and phosphorylation by the G protein-coupled receptor kinases. They play an essential role in receptor desensitization and endocytosis, a ... Full text Link to item Cite

Generation, characterization and crystallization of a highly active and stable cytochrome bc1 complex mutant from Rhodobacter sphaeroides.

Journal Article Biochim Biophys Acta · July 2006 Featured Publication The availability of the three dimensional structure of mitochondrial enzyme, obtained by X-ray crystallography, allowed a significant progress in the understanding of the structure-function relation of the cytochrome bc(1) complex. Most of the structural i ... Full text Link to item Cite

beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor.

Journal Article J Biol Chem · January 13, 2006 Featured Publication Physiological effects of beta adrenergic receptor (beta2AR) stimulation have been classically shown to result from G(s)-dependent adenylyl cyclase activation. Here we demonstrate a novel signaling mechanism wherein beta-arrestins mediate beta2AR signaling ... Full text Link to item Cite

Activation-dependent conformational changes in {beta}-arrestin 2.

Journal Article J Biol Chem · December 31, 2004 Featured Publication Beta-arrestins are multifunctional adaptor proteins, which mediate desensitization, endocytosis, and alternate signaling pathways of seven membrane-spanning receptors (7MSRs). Crystal structures of the basal inactive state of visual arrestin (arrestin 1) a ... Full text Link to item Cite

The extra fragment of the iron-sulfur protein (residues 96-107) of Rhodobacter sphaeroides cytochrome bc1 complex is required for protein stability.

Journal Article Biochemistry · February 17, 2004 Featured Publication Sequence alignment of the Rieske iron-sulfur protein (ISP) of cytochrome bc(1) complex from various sources reveals that bacterial ISPs contain an extra fragment. To study the role of this fragment in bacterial cytochrome bc(1) complex, Rhodobacter sphaero ... Full text Link to item Cite

Effect of famoxadone on photoinduced electron transfer between the iron-sulfur center and cytochrome c1 in the cytochrome bc1 complex.

Journal Article J Biol Chem · March 28, 2003 Featured Publication Famoxadone is a new cytochrome bc(1) Q(o) site inhibitor that immobilizes the iron-sulfur protein (ISP) in the b conformation. The effects of famoxadone on electron transfer between the iron-sulfur center (2Fe-2S) and cyt c(1) were studied using a rutheniu ... Full text Link to item Cite

Design of a ruthenium-labeled cytochrome c derivative to study electron transfer with the cytochrome bc1 complex.

Journal Article Biochemistry · March 18, 2003 A new ruthenium-cytochrome c derivative was designed to study electron transfer from cytochrome bc1 to cytochrome c (Cc). The single sulfhydryl on yeast H39C;C102T iso-1-Cc was labeled with Ru(2,2'-bipyrazine)2(4-bromomethyl-4'-methyl-2,2'-bipyridine) to f ... Full text Link to item Cite

Inter- and intra-molecular electron transfer in the cytochrome bc(1) complex.

Journal Article Biochim Biophys Acta · September 10, 2002 In this review, we compare the intra-molecular and inter-molecular electron transfer rate constants of the high-potential branch of the cytochrome bc(1) complex. Several methods such as the conventional stopped-flow spectroscopy, pH-induced electron transf ... Full text Link to item Cite

Photoinduced electron transfer between the Rieske iron-sulfur protein and cytochrome c(1) in the Rhodobacter sphaeroides cytochrome bc(1) complex. Effects of pH, temperature, and driving force.

Journal Article J Biol Chem · August 23, 2002 Electron transfer from the Rieske iron-sulfur protein to cytochrome c(1) (cyt c(1)) in the Rhodobacter sphaeroides cytochrome bc(1) complex was studied using a ruthenium dimer complex, Ru(2)D. Laser flash photolysis of a solution containing reduced cyt bc( ... Full text Link to item Cite

Evidence for the intertwined dimer of the cytochrome bc(1) complex in solution.

Journal Article J Biol Chem · December 7, 2001 Featured Publication To confirm that the cytochrome bc(1) complex exists as a dimer with intertwining Rieske iron-sulfur proteins in solution, four Rhodobacter sphaeroides mutants expressing His-tagged cytochrome bc(1) complexes containing two pairs of cysteine substitutions, ... Full text Link to item Cite

Confirmation of the involvement of protein domain movement during the catalytic cycle of the cytochrome bc1 complex by the formation of an intersubunit disulfide bond between cytochrome b and the iron-sulfur protein.

Journal Article J Biol Chem · December 8, 2000 Featured Publication To study the essentiality of head domain movement of the Rieske iron-sulfur protein (ISP) during bc(1) catalysis, Rhodobacter sphaeroides mutants expressing His-tagged cytochrome bc(1) complexes with three pairs of cysteines engineered (one cysteine each) ... Full text Link to item Cite