Abstract:
:The oligomerization and aggregation of the amyloid-beta (A beta) peptide, a cleavage product of the amyloid precursor protein predominantly 40 or 42 amino acids in length, has been implicated in the pathogenesis of Alzheimer's disease. The identification of A beta-binding agents, e.g., antibodies or peptides, constitutes a promising therapeutic approach. However, the amount of structural and biophysical data on the underlying A beta interactions is currently very limited. We have earlier determined the structure of A beta (1-40) in complex with the affibody protein Z(A beta 3), a selected binding protein based on a three-helix bundle scaffold (Z domain). Z(A beta 3) is a dimer of affibody subunits linked via a disulfide bridge involving a selected cysteine mutation at position 28. Z(A beta 3) binds to the central and C-terminal part of A beta (residues 17-36), which adopts a beta-hairpin conformation in the complex. Here we present a detailed biophysical analysis of the Z(A beta 3):A beta (1-40) interaction, employing NMR, circular dichroism spectroscopy, 8-anilino-1-naphthalenesulfonic acid and tyrosine fluorescence, size-exclusion chromatography, thermal denaturation profiles and isothermal titration calorimetry. We conclude that (i) free Z(A beta 3) is characterized by conformational exchange and the loss of helix 1 of the three-helix bundle scaffold; (ii) a high-energy barrier is associated with the conversion of an initial Z(A beta 3):A beta (1-40) recognition complex into the native complex structure, entailing slow binding kinetics; (iii) both A beta and Z(A beta 3) fold upon binding, which, e.g., becomes manifest in the binding thermodynamics that feature a large negative change in heat capacity; (iv) the C28-disulfide does not merely afford dimerization, but its impact on the binding interfaces of the affibody subunits and A beta is a prerequisite for tight binding. The extensive folding coupled to binding observed here likely constitutes an obligate feature of biomolecular interactions involving the central and C-terminal part of A beta. Options for improvement of Z(A beta) binding proteins are discussed.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Hoyer W,Härd Tdoi
10.1016/j.jmb.2008.02.040subject
Has Abstractpub_date
2008-04-25 00:00:00pages
398-411issue
2eissn
0022-2836issn
1089-8638pii
S0022-2836(08)00237-4journal_volume
378pub_type
杂志文章abstract::The crystal structure of a construct consisting of the FERM and SH2-like domains of the human Janus kinase 1 (JAK1) bound to a fragment of the intracellular domain of the interferon-λ receptor 1 (IFNLR1) has been determined at the nominal resolution of 2.1Å. In this structure, the receptor peptide forms an 85-Å-long e...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2016.10.005
更新日期:2016-11-20 00:00:00
abstract::At low ionic strength, the SfiI restriction enzyme cleaved at similar rates both supercoiled and linear DNA with two SfiI sites and linear DNA with one SfiI site. For the substrates with two sites, the majority of the DNA was converted directly to products cut at both sites; the enzyme appears to bind to two sites bef...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.1995.0506
更新日期:1995-09-29 00:00:00
abstract::A number of beta-sandwich immunoglobulin-like domains have been shown to fold using a set of structurally equivalent residues that form a folding nucleus deep within the core of the protein. Formation of this nucleus is sufficient to establish the complex Greek key topology of the native state. These nucleating residu...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2007.09.088
更新日期:2008-01-11 00:00:00
abstract::Mutations at solvent-inaccessible core positions in proteins can impact function through many biophysical mechanisms including alterations to thermodynamic stability and protein dynamics. As these properties of proteins are difficult to investigate, the impacts of core mutations on protein function are poorly understo...
journal_title:Journal of molecular biology
pub_type: 评论,杂志文章
doi:10.1016/j.jmb.2013.10.042
更新日期:2014-04-03 00:00:00
abstract::Signaling photoreceptors mediate diverse organismal adaptations in response to light. As light-gated protein switches, signaling photoreceptors provide the basis for optogenetics, a term that refers to the control of organismal physiology and behavior by light. We establish as novel optogenetic tools the plasmids pDus...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2012.01.001
更新日期:2012-03-02 00:00:00
abstract::Histone deacetylases (HDACs) modify core histones and participate in large regulatory complexes that both suppress and enhance transcription. Recent studies indicate that some HDACs can act on non-histone proteins as well. Interest in these enzymes is growing because HDAC inhibitors appear to be promising therapeutic ...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2004.02.006
更新日期:2004-04-16 00:00:00
abstract::We have identified a novel family of proteins, in which the N-terminal cystathionine beta-synthase (CBS) domain is fused to the C-terminal Zn ribbon domain. Four proteins were overexpressed in Escherichia coli and purified: TA0289 from Thermoplasma acidophilum, TV1335 from Thermoplasma volcanium, PF1953 from Pyrococcu...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2007.10.060
更新日期:2008-01-04 00:00:00
abstract::In the prokaryotic homolog of the eukaryotic proteasome, HslUV, the "double donut" HslV protease is allosterically activated by HslU, an AAA protein of the Clp/Hsp100 family consisting of three (amino-terminal, carboxy-terminal, and intermediate) domains. The intermediate domains of HslU, which extend like tentacles f...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/s0022-2836(03)00580-1
更新日期:2003-07-04 00:00:00
abstract::We quantify the degree to which folding occurs along a complex landscape with structurally distinct pathways using psi-analysis in combination with a protein engineering method that identifies native, non-covalent polypeptide interactions and their relative populations at the rate-limiting step. By probing the proximi...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2004.01.018
更新日期:2004-03-19 00:00:00
abstract::A common feature of many of the most important and prominent amyloid-forming proteins is their ability to bind lipids and lipid complexes. Lipids are ubiquitous components of disease-associated amyloid plaques and deposits in humans, yet the specific roles of lipid in the process of amyloid fibril formation are poorly...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2007.10.038
更新日期:2008-01-04 00:00:00
abstract::We describe the physicochemical characterization of various circular and linear forms of the approximately 60 residue N-terminal Src homology 3 (SH3) domain from the murine c-Crk adapter protein. Structural, dynamic, thermodynamic, kinetic and biochemical studies reveal that backbone circularization does not prevent t...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.2001.4631
更新日期:2001-05-18 00:00:00
abstract::HBII-52 is a human brain-specific C/D box snoRNA that potentially regulates the editing and/or alternative splicing of the serotonin receptor. Forty-two nearly identical copies of the HBII-52 gene are located immediately downstream of the SNRPN protein-coding gene in an imprinted locus associated with Prader-Willi syn...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2008.06.057
更新日期:2008-09-12 00:00:00
abstract::Profilins are small proteins capable of binding actin, poly-l-proline and other proline-rich sequences, and phosphatidylinositol (4,5)-bisphosphate. A number of proline-rich ligands for profilin have been characterised, including proteins of the Ena/VASP and formin families. We have determined the high-resolution crys...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2007.10.050
更新日期:2008-01-04 00:00:00
abstract::The four approximately 75-residue domains (repeats) that constitute the annexin core structure all possess an identical five-alpha-helix bundle topology, but the physico-chemical properties of the isolated domains are different. Domain IV of the annexins has previously been expressed only as inclusion bodies, resistan...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2006.08.042
更新日期:2006-10-20 00:00:00
abstract::MEF2 and NKX2-5 transcription factors interact with each other in cardiogenesis and are necessary for normal heart formation. Despite evidence suggesting that these two transcription factors function synergistically and possibly through direct physical interactions, molecular mechanisms by which they interact are not ...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2020.07.004
更新日期:2020-09-04 00:00:00
abstract::Bacteriophage λ of Escherichia coli has two alternative life cycles after infection-host survival with lysogen formation, or host lysis and phage production. In a lysogen, CI represses the two lytic promoters, pR and pL, and activates its own transcription from the auto-regulated pRM promoter. During induction from th...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2017.11.005
更新日期:2018-01-05 00:00:00
abstract::Pancreatic amyloid is found in more than 95 % of type II diabetes patients. Pancreatic amyloid is formed by the aggregation of islet amyloid polypeptide (hIAPP or amylin), which is a 37-residue peptide. Because pancreatic amyloid is cytotoxic, it is believed that its formation is directly associated with the developme...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.1999.3422
更新日期:2000-01-28 00:00:00
abstract::Homodimeric bone morphogenetic protein-2 (BMP-2) is a member of the transforming growth factor beta (TGF-beta) superfamily that induces bone formation and regeneration, and determines important steps during early stages of embryonic development in vertebrates and non-vertebrates. BMP-2 can interact with two types of r...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.1999.2590
更新日期:1999-03-19 00:00:00
abstract::The comet motility assay, inspired by Listeria locomotion, has been used extensively as an in vitro model to study the structural and motile properties of the actin cytoskeleton. However, there are no quantitative measurements of the mechanical properties of these actin comets. In this work, we use nanoindentation bas...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2011.08.054
更新日期:2011-10-28 00:00:00
abstract::The catalytic pentad of tyrosine recombinases, that assists the tyrosine nucleophile, includes a conserved histidine/tryptophan (His/Trp-III). Flp and Cre harbor tryptophan at this position; most of their kin recombinases display histidine. Contrary to the conservation rule, Flp(W330F) is a much stronger recombinase t...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2007.02.022
更新日期:2007-04-20 00:00:00
abstract::Functional large ribosomal subunits of Thermus aquaticus can be reconstituted from ribosomal proteins and either natural or in vitro transcribed 23 S and 5 S rRNA. Omission of 5 S rRNA during subunit reconstitution results in dramatic decrease of the peptidyl transferase activity of the assembled subunits. However, th...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.1999.3030
更新日期:1999-09-03 00:00:00
abstract::The oxyR-encoded regulatory protein, OxyR, acts to induce the synthesis of a family of hydrogen peroxide-inducible proteins in Salmonella typhimurium and Escherichia coli. To further define the mechanism by which oxyR regulates the production of these proteins, we identified, mapped, and characterized oxyR-regulated p...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/0022-2836(89)90104-6
更新日期:1989-12-20 00:00:00
abstract::Understanding the interaction of Arf and Hdm2 has recently become a central issue in cancer biology. In response to hyperproliferative signals, p14(Arf) stabilizes p53 by binding to Hdm2 and inhibits the ubiquitination and subsequent proteosome-dependent degradation of p53. The medical importance of the Arf-Hdm2-p53 r...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.2001.5110
更新日期:2001-11-23 00:00:00
abstract::We have determined the X-ray crystallographic structure of trout Hb I in both the deoxy and carbonmonoxy forms to resolution limits of 2.3 angstroms and 2.5 angstroms, respectively. The overall fold of the molecule is highly similar to that of human HbA despite the low level of sequence identity between these proteins...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.1996.0355
更新日期:1996-06-21 00:00:00
abstract::Cardiovascular homeostasis and blood pressure regulation are reliant, in part, on interactions between natriuretic peptide (NP) hormones and natriuretic peptide receptors (NPR). The C-type NPR (NPR-C) is responsible for clearance of NP hormones from the circulation, and displays a cross-reactivity for all NP hormones ...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2006.06.060
更新日期:2006-08-25 00:00:00
abstract::Single-strand conformers (SSCs) from the C-rich strand of the triplet repeat at the FMR-1 locus are rapidly and selectively methylated by the human DNA (cytosine-5) methyltransferase. The apparent affinity of the enzyme for the FMR-1 SSC is about tenfold higher than it is for a control Watson-Crick paired duplex. The ...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.1997.1430
更新日期:1998-01-09 00:00:00
abstract::KorA and KorB proteins of IncP1 plasmid RK2 are encoded in the central control region (ccr) of the plasmid and act as global regulators of plasmid genes for replication, transfer and stable inheritance. KorA represses seven promoters on RK2, by binding to a defined operator site, OA, which always occurs in promoter re...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.1999.2761
更新日期:1999-06-04 00:00:00
abstract::Human kallikrein 5 (hK5) is a member of the tissue kallikrein family of serine peptidases. It has trypsin-like substrate specificity, is inhibited by metal ions, and is abundantly expressed in human skin, where it is believed to play a central role in desquamation. To further understand the interaction of hK5 with sub...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2007.08.042
更新日期:2007-11-02 00:00:00
abstract::The crystal structures of three vancomycin complexes with two vancomycin-sensitive cell-wall precursor analogs (diacetyl-Lys-D-Ala-D-Ala and acetyl-D-Ala-D-Ala) and a vancomycin-resistant cell-wall precursor analog (diacetyl-Lys-D-Ala-D-lactate) were determined at atomic resolutions of 1.80 A, 1.07 A, and 0.93 A, resp...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2008.10.026
更新日期:2009-02-06 00:00:00
abstract::The mitochondrial inner membrane consists of two morphologically distinct domains, the inner boundary membrane and large invaginations termed cristae. Narrow membrane structures, the crista junctions, link these two domains. Maintenance of this elaborate architecture depends on the evolutionarily conserved mitochondri...
journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1016/j.jmb.2016.02.031
更新日期:2016-04-24 00:00:00