Jordan H Chill

• PhD
• Professor (Associate) at Bar Ilan University

Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer’s disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1) self-assemble into cross β-sheet nanotubes, react with early Aβ species (1-3 mers), and inhibit Aβ aggregation and toxicity in stoichiometric...

Dynamic oscillations in the phosphorylation and ubiquitination of key proliferative regulators are defining features of the eukaryotic cell cycle. Resetting the cell cycle at the mitosis-to-G1 transition requires activation of the E3 ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C), which ensures cell cycle irreversibility by targeting...

Dysfunction of the human voltage‐gated K⁺ channel Kv1.1 has been associated with epilepsy, multiple sclerosis, episodic ataxia, myokymia, and cardiorespiratory dysregulation. We report here that AETX‐K, a sea anemone type I (SAK1) peptide toxin we isolated from a phage display library, blocks Kv1.1 with high affinity (Ki ~ 1.6 pM) and notable speci...

Inspired by the role of intracellular liquid-liquid phase separation (LLPS) in formation of membraneless organelles, there is great interest in developing dynamic compartments formed by LLPS of intrinsically disordered proteins (IDPs) or short peptides. However, the molecular mechanisms underlying the formation of biomolecular condensates have not...

Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer’s disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1 ) self-assemble into cross β-sheet nanotubes, react with early Aβ species (1-3 mers), and inhibit Aβ aggregation and toxicity in stoichiometri...

Dissemination of cancer cells from the primary tumor into distant body tissues and organs is the leading cause of death in cancer patients. While most clinical strategies aim to reduce or impede the growth of the primary tumor, no treatment to eradicate metastatic cancer exists at present. Metastasis is mediated by feet-like cytoskeletal structures...

Inspired by the role of intracellular liquid-liquid phase separation (LLPS) in formation of membraneless organelles, there is great interest in developing dynamic compartments formed by LLPS of intrinsically disordered proteins (IDPs) or short peptides. However, the molecular mechanisms underlying the formation of such biomolecular condensates have...

The pathogen Bordetella pertussis uses a type-3 secretion system (T3SS) to inject its cytotoxic effector BteA into the host cell via a designated needle structure. Prior to injection BteA is bound to its cognate chaperone BtcA presumed to assist in effector unfolding en route to needle passage. We utilized NMR and EPR spectroscopy to uncover the mo...

Class I WW domains are present in many proteins of various functions and mediate protein interactions by binding to short linear PPxY motifs. Tandem WW domains often bind peptides with multiple PPxY motifs, but the interplay of WW-peptide interactions is not always intuitive. The WW domain-containing oxidoreductase (WWOX) harbors two WW domains: an...

The non-receptor tyrosine kinase Pyk2 is highly expressed in breast cancer, where it mediates invadopodia formation and function via interaction with the actin-nucleation promoting factor cortactin. Here, we designed a cell-permeable peptide inhibitor that contains the second proline-rich region (PRR2) sequence of Pyk2, which binds to the SH3 domai...

Class I WW domains mediate protein interactions by binding short linear PPxY motifs. They occur predominantly as tandem repeats, and their target proteins often contain multiple PPxY motifs, but the interplay of WW/peptide interactions is not always intuitive. WW domain-containing oxidoreductase (WWOX) protein harbors two WW domains: unstable WW1 c...

RGD sequence is a tripeptide composed of three amino acids: arginine (R), glycine (G), and aspartic acid (D). The RGD peptide has a high affinity to the integrin alpha v beta 3, which is overexpressed on the membrane of many cancer cells and is attracted to areas of angiogenesis. Proteinoids are biodegradable polymers based on amino acids which are...

WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function from cell biology studies, summarized in...

We show here that membrane-tethered toxins facilitate the biophysical study of the roles of toxin residues in K ⁺ channel blockade to reveal two blocking mechanisms in the K ⁺ channel pore. The structure of the sea anemone type I (SAK1) toxin HmK is determined by NMR. T-HmK residues are scanned by point mutation to map the toxin surface, and seven...

Membrane‐embedded proteins (MPs) are central to a wide range of cellular processes. Despite their importance, structural studies of MPs are hindered by expression difficulties and the need for stabilization in a membrane‐mimicking environment. High‐resolution NMR methods can investigate structure and function of MPs due to methodological advances a...

BteA, a 69-kDa cytotoxic protein, is a type III secretion system (T3SS) effector in the classical Bordetella, the etiological agents of pertussis and related mammalian respiratory diseases. Like other cytotoxicity-mediating effectors, BteA uses its multifunctional N-terminal domain to target phosphatidylinositol (PI)-rich microdomains in the host m...

Fog formation on transparent surfaces constitutes a major challenge in several optical applications, such as plastic packaging, lenses, mirrors, and windshields. To overcome this problem, we prepared and characterized durable antifog thin coatings on plastic films such as polyethylene terephthalate (PET). Proteinoids are biocompatible random polyme...

The bacterial potassium channel KcsA is gated by pH, opening for conduction under acidic conditions. Molecular determinants responsible for this effect have been identified at the extracellular selectivity filter, at the membrane-cytoplasm interface (TM2-gate), and in the cytoplasmic C-terminal domain (CTD), an amphiphilic four-helix bundle mediate...

The bacterial potassium channel KcsA is gated by pH, opening for conduction under acidic conditions. Molecular determinants responsible for this effect have been identified at the extracellular selectivity filter, at the membrane–cytoplasm interface (TM2 gate), and in the cytoplasmic C‐terminal domain (CTD), an amphiphilic four‐helix bundle mediate...

Helices are key structural features in biopolymers, enabling a variety of biological functions. Mimicking these secondary structure motifs has a wide potential in the development of biomimetic materials. Peptoids, N-substituted glycine oligomers, are an important class of peptide mimics that can adopt polyproline type helices if the majority of the...

Aggregation and accumulation of amyloid β and tau proteins to plaques and neurofibrillary tangles are the key pathogenic events in Alzheimer's disease. Here, we studied the capability of the cyclic...

Wiskott-Aldrich syndrome protein (WASp) is exclusively expressed in hematopoietic cells and responsible for actin-dependent processes, including cellular activation, migration and invasiveness. The C-terminal domain of WASp-Interacting Protein (WIP) binds to WASp and regulates its activity by shielding it from degradation in a phosphorylation depen...

Wiskott–Aldrich syndrome protein (WASp) is exclusively expressed in hematopoietic cells and responsible for actin-dependent processes, including cellular activation, migration, and invasiveness. The C-terminal domain of WASp-Interacting Protein (WIP) binds to WASp and regulates its activity by shielding it from degradation in a phosphorylation depe...

Peptide neurotoxins are powerful tools for research, diagnosis and treatment of disease. Limiting broader use, most receptors lack an identified toxin that binds with high-affinity and specificity. Here we describe isolation of toxins for one such orphan target, KcsA, a K+ channel that has been fundamental to delineating the structural basis for io...

Intrinsically disordered proteins (IDPs) are multi-conformational polypeptides that lack a single stable three-dimensional structure. It has become increasingly clear that the versatile IDPs play key roles in a multitude of biological processes, and, given their flexible nature, NMR is a leading method to investigate IDP behavior on the molecular l...

Understanding the human copper cycle is essential in order to understand the role of metals in promoting neurological diseases and disorders. One of the cycles controlling the cellular concentration and distribution of copper involves the copper transporter, Ctr1, the metallochaperone, Atox1, and the ATP7B transporter. It has been shown that the C-...

Cation diffusion facilitators (CDF) are highly conserved, metal ion efflux transporters that maintain divalent transition metal cation homeostasis. Most CDF proteins contain two domains, the cation transporting transmembrane domain and the regulatory cytoplasmic C-terminal domain (CTD). MamM is a magnetosome-associated CDF protein essential for the...

Many peptides and proteins with large sequences and structural differences self-assemble into disease-causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross-interaction. Here, we demonstrate how the self-assembled, cyclic d,l-α-peptide CP-2, which has similar structural and function...

Intrinsically disordered proteins (IDPs) are multi-conformational polypeptides that lack a stable three-dimensional structure, forcing structural biology to reconsider the structure-function paradigm. The versatile IDPs play key roles in a multitude of biological processes, and, given their inherently flexible nature, nuclear magnetic resonance (NM...

Significance Peptide neurotoxins that inhibit specific ion channels are valuable for research and clinical care but unknown for most targets. Here we consider KcsA, an orphan potassium channel with no known toxin. We build a phage-display library expressing natural toxins related to the sea anemone toxin ShK and 1.5 million novel combinatorial vari...

The 35-residue ShK peptide binds with high affinity to voltage-gated potassium channels. The dynamics of the binding surface was studied recently with (15)N relaxation dispersion (μs-ms) and (15)N spin relaxation (ps-ns) of the backbone amide bonds. Relaxation dispersion revealed μs conformational-exchange-mediated exposure of the functionally impo...

Assembly of aSyn into neurotoxic oligomers and amyloid fibrils is a pathogenic feature of Parkinson's disease and related synucleinophaties. This natively disordered protein undergoes misfolding and subsequent aggregation, and deposits in Lewy bodies lesions, leading to pathological symptoms. Given the significant structural and functional similari...

The intracellular C-terminal domain (CTD) of KcsA, a bacterial homotetrameric potassium channel, is a 40-residue long segment which natively adopts a helical bundle conformation with four-fold symmetry. A hallmark of KcsA behavior is a pH-induced conformational change which leads to opening of the channel at acidic pH. While crystal structures of f...

WASp-interacting protein (WIP) is an intrinsically disordered 503-residue polypeptide with a key role in actin polymerization in activated T cells. Its interaction with actin is mediated by a pair of conserved actin binding motifs (ABMs) at the WIP N-terminus, a domain that has not been investigated in its unbound form. Here we use nuclear magnetic...

DNA molecules were recently converted using ultrasonic irradiation into microcapsules that can trap hydrophobic molecules in aqueous solution. These DNA microcapsules are able to penetrate prokaryotic and eukaryotic cells, deliver drugs and transfer genetic information e.g. for protein expression into the host cells. DNA of different sizes and stru...

ShK is a 35-residue peptide that binds with high affinity to human voltage-gated potassium channels through a conserved K-Y dyad. Here we have employed NMR measurements of backbone-amide 15N spin-relaxation rates to investigate motions of the ShK backbone. Although ShK is rigid on the ps to ns timescale, increased linewidths observed for 11 backbon...

The cover picture shows NMR detecting previously unobserved backbone motions of the 35-residue marine potassium channel blocker ShK. By measuring the relaxation of 15N magnetic moments of ShK (PDB ID: 1roo, shown as a white surface) under different experimental conditions, the existence of a lowly populated conformer was inferred. As described in t...

The cytoplasmic C-terminal domain (CTD) of KcsA, a bacterial homotetrameric potassium channel, is an amphiphilic domain that forms a helical bundle with four-fold symmetry mediated by hydrophobic and electrostatic interactions. Previously we have established that a CTD-derived 34-residue peptide associates into a tetramer in a pH-dependent manner [...

E1 and E2 are two hepatitis C viral envelope glycoproteins that assemble into a heterodimer that is essential for membrane fusion and penetration into the target cell. Both extracellular and transmembrane (TM) glycoprotein domains contribute to this interaction, but study of TM-TM interactions has been limited because synthesis and structural chara...

Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeletal machinery. Binding of WASp-interacting protein (WIP) to WASp modulates WASp activity and protects it from degradation. Formation of the WIP-WASp complex is crucial for the adaptive immune response. We found that WIP and WASp interacted in cells through two distinct...

Bordetella pertussis, the etiological agent of "whooping cough" disease, utilizes the type III secretion system (T3SS) to deliver a 69 kDa cytotoxic effector protein, BteA, directly into the host cells. As with other T3SS effectors, prior to its secretion BteA binds BtcA, a 13.9 kDa protein predicted to act as a T3SS class IA chaperone. While this...

Oligomerization of hepatitis C viral envelope proteins E1 and E2 is essential to virus fusion and assembly. Although interactions within the transmembrane (TM) domains of these glycoproteins have proven contributions to the E1/E2 heterodimerization process and consequent infectivity, there is little structural information on this entry mechanism. H...

Oxidative stress directly correlates with the early onset of vascular complications and the progression of peripheral insulin resistance in diabetes. Accordingly, exogenous antioxidants augment insulin sensitivity in type 2 diabetic patients and ameliorate its clinical signs. Herein, we explored the unique structural and functional properties of th...

WASp-interacting protein (WIP) is a 503-residue proline-rich polypeptide expressed in human T cells. The WIP C-terminal domain binds to Wiskott-Aldrich syndrome protein (WASp) and regulates its activation and degradation, and the WIP-WASp interaction has been shown to be critical for actin polymerization and implicated in the onset of WAS and X-lin...

BteA, a 69-kDa cytotoxic protein, is a type III secretion system (T3SS) effector in the classical Bordetella, the etiological agents of pertussis and related mammalian respiratory diseases. Currently there is limited information regarding the structure of BteA or its subdomains, and no insight as to the identity of its eukaryotic partners(s) and th...

SAXS experiment of BteA287 at 10 mg/ml. Experimental data of BteA287 at 10 mg/ml. Inset, Guinier plot (squares) with fitted correlation line (red). (TIF)

BteA287 limited proteolysis with Trypsin. Purified BteA287 was mixed with 1.5 mg/ml of Trypsin at a ratio of 1:5000 and incubated at room temperature for the indicated time points at which the reaction was quenched with equal volume of sample buffer. Samples were resolved on a 17.5% SDS-PAGE and stained with coomassie blue stain. (TIF)

Carbon-13 direct-detection NMR methods have proved to be very useful for the characterization of intrinsically disordered proteins (IDPs). Here we present a suite of experiments in which amino-acid-selective editing blocks are encoded in CACON- and CANCO-type sequences to give (13) C-detected spectra containing correlations arising from a particula...

The inside cover picture shows how “spin gymnastics” can be used to “avoid the crowd”. A major problem with the NMR spectra of intrinsically disordered proteins is the chemical shift dispersion arising from their high flexibility and lack of unique 3D structure. On p. 2425 ff., I. C. Felli, R. Pierattelli, et al. present a strategy for drastically...

A pair of 4D NMR experiments for the backbone assignment of disordered proteins is presented. The experiments exploit (13)C direct detection and non-uniform sampling of the indirectly detected dimensions, and provide correlations of the aliphatic proton (H(α), and H(β)) and carbon (C(α), C(β)) resonance frequencies to the protein backbone. Thus, al...

The intracellular C-terminal domain (CTD) of KcsA, a bacterial homotetrameric potassium channel, is a 40-residue-long segment that natively adopts a helical bundle conformation with 4-fold symmetry. A hallmark of KcsA behavior is pH-induced conformational change, which leads to the opening of the channel at acidic pH. Previous studies have reached...

Structure determination of membrane-associated proteins (MPs) represents a frontier of structural biology that is characterized by unique challenges in sample preparation and data acquisition. No less important is our ability to study the dynamics of MPs, since MP flexibility and characteristic motions often make sizeable contributions to their fun...

Spectral simplicity of solution NMR spectra results from the Brownian rotational diffusion of solutes, which rapidly averages the strong dipolar interactions between different spins to exactly zero. Much valuable structural information, contained in these dipolar interactions, is lost in this averaging process. It has long been known that alignment...

KcsA is a homotetrameric 68-kDa membrane-associated potassium channel which selectively gates the flux of potassium ions across the membrane. The channel is known to undergo a pH-dependent open-to-closed transition. Here we describe an NMR study of the monomeric subunit of the channel (KcsAM), solubilized in SDS micelles. Chemical shift, solvent ex...

A new strategy is demonstrated that simultaneously enhances sensitivity and resolution in three- or higher-dimensional heteronuclear multiple quantum NMR experiments. The approach, referred to as mixed-time parallel evolution (MT-PARE), utilizes evolution of chemical shifts of the spins participating in the multiple quantum coherence in parallel, t...

Type I interferons (IFNs) are a family of homologous helical cytokines that exhibit pleiotropic effects on a wide variety of cell types, including antiviral activity and antibacterial, antiprozoal, immunomodulatory, and cell growth regulatory functions. Consequently, IFNs are the human proteins most widely used in the treatment of several kinds of...

A set of TROSY-HNCO (tHNCO)-based 3D experiments is presented for measuring (15)N relaxation parameters in large, membrane-associated proteins, characterized by slow tumbling times and significant spectral overlap. Measurement of backbone (15)N R (1), R (1rho), (15)N-{(1)H} NOE, and (15)N CSA/dipolar cross correlation is demonstrated and applied to...

Nuclear magnetic resonance (NMR) studies of large membrane-associated proteins are limited by the difficulties in preparation of stable protein-detergent mixed micelles and by line broadening, which is typical of these macroassemblies. We have used the 68-kDa homotetrameric KcsA, a thermostable N-terminal deletion mutant of a bacterial potassium ch...

A method for the measurement of proton T(1)(rho) relaxation times in unlabeled proteins is described using a variable spin-lock pulse after the initial nonselective 90 degrees excitation in a HOHAHA pulse sequence. The experiment is applied to alpha-bungarotoxin (alpha-BTX) and its complex with a 25-residue peptide derived from the acetylcholine re...

Human monoclonal antibody (mAb) 447-52D neutralizes a broad spectrum of HIV-1 isolates, whereas murine mAb 0.5beta, raised against gp120 of the X4 isolate HIV-1(IIIB), neutralizes this strain specifically. Two distinct gp120 V3 peptides, V3(MN) and V3(IIIB), adopt alternative beta-hairpin conformations when bound to 447-52D and 0.5beta, respectivel...

The antiviral and antiproliferative activities of type I interferons (IFNs) are mediated by a common receptor, and its second subunit (IFNAR2) exhibits nanomolar affinity to both IFNalpha and IFNbeta subtypes. We have previously determined the structure of the IFN-binding extracellular domain of IFNAR2 (IFNAR2-EC) using multidimensional NMR [Chill,...

The potent antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by a single receptor comprising two subunits, IFNAR1 and IFNAR2. The structure of the IFNAR2 IFN binding ectodomain (IFNAR2-EC), the first helical cytokine receptor structure determined in solution, reveals the molecular basis for IFN binding. The...

The potent antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by a single receptor comprising two subunits, IFNAR1 and IFNAR2. The structure of the IFNAR2 IFN binding ectodomain (IFNAR2-EC), the first helical cytokine receptor structure determined in solution, reveals the molecular basis for IFN binding. The...

The structure of a peptide corresponding to residues 182-202 of the acetylcholine receptor alpha1 subunit in complex with alpha-bungarotoxin was solved using NMR spectroscopy. The peptide contains the complete sequence of the major determinant of AChR involved in alpha-bungarotoxin binding. One face of the long beta hairpin formed by the AChR pepti...

The α subunit of the nicotinic acetylcholine receptor (AChR) from Torpedo electric organ and mammalian muscle contains high affinity binding sites for α-bungarotoxin and for autoimmune antibodies in sera of patients with myasthenia gravis. To obtain sufficient materials for structural studies of the receptor-ligand complexes, we have expressed part...

The human interferon receptor (IFNAR) mediates the antiviral and antiproliferative activities of type I interferons (IFNs). This receptor is comprised of subunits IFNAR1 and IFNAR2, the latter exhibiting nanomolar affinity for IFNs. Here the extracellular domain of IFNAR2 (IFNAR2-EC), a soluble 25 kDa IFN-binding polypeptide, and its complex with I...

The alpha-subunit of the nicotinic acetylcholine receptor (alphaAChR) contains a binding site for alpha-bungarotoxin (alpha-BTX), a snake-venom-derived alpha-neurotoxin. Previous studies have established that the segment comprising residues 173-204 of alphaAChR contains the major determinant interacting with the toxin, but the precise boundaries of...