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Conformational Plasticity (conformational + plasticity)
Selected AbstractsThe capsid protein of human immunodeficiency virus: intersubunit interactions during virus assemblyFEBS JOURNAL, Issue 21 2009Mauricio G. Mateu The capsid protein (CA) of HIV-1 is composed of two domains, the N-terminal domain (NTD) and the C-terminal domain (CTD). During the assembly of the immature HIV-1 particle, both CA domains constitute a part of the Gag polyprotein, which forms a spherical capsid comprising up to 5000 radially arranged, extended subunits. Gag,Gag interactions in the immature capsid are mediated in large part by interactions between CA domains, which are involved in the formation of a lattice of connected Gag hexamers. After Gag proteolysis during virus maturation, the CA protein is released, and approximately 1000,1500 free CA subunits self-assemble into a truncated cone-shaped capsid. In the mature capsid, NTD,NTD and NTD,CTD interfaces are involved in the formation of CA hexamers, and CTD,CTD interfaces connect neighboring hexamers through homodimerization. The CA,CA interfaces involved in the assembly of the immature capsid and those forming the mature capsid are different, at least in part. CA appears to have evolved an extraordinary conformational plasticity, which allows the creation of multiple CA,CA interfaces and the occurrence of CA conformational switches. This minireview focuses on recent structure,function studies of the diverse CA,CA interactions and interfaces involved in HIV-1 assembly. Those studies are leading to a better understanding of molecular recognition events during virus morphogenesis, and are also relevant for the development of anti-HIV drugs that are able to interfere with capsid assembly or disassembly. [source] Probing ligand-induced conformational changes of human CD38FEBS JOURNAL, Issue 10 2000Valérie Berthelier The lymphoid surface antigen CD38 is basically a NAD+glycohydrolase, which is also involved in the metabolism of cyclic ADP-ribose. Besides, this ecto-enzyme has potential signalling roles in T- and B-cells. Such multiple functions prompted us to study the molecular dynamics of the CD38 protein and especially the relationship between its ecto-enzymatic active site and its epitope, i.e. the binding site of most known anti-CD38 monoclonal antibodies. Both epitopic and enzymatic sites were shown to be degraded by proteases, such as trypsin or chymotrypsin. This sensitivity was almost entirely suppressed in the presence of substrates or inhibitors. Both sites were also degraded in the presence of reducing agents, as dithiothreitol. Inhibitory ligands induced the same resistance of both sites against reducing attack. The binding of CD38 ligands to the active site triggers therefore conformational changes that shield some backbone bonds and disulfide bridges against, respectively, proteolytic cleavage or reduction. This transconformation was found moreover to irreversibly take place after incubation with substrates such as NAD+ in the presence of dithiothreitol. The epitope remained preserved, while the enzymatic activity was lost. This inactivation probably resulted from the covalent trapping of the catalytically reactive intermediate in the active site (i.e. paracatalytic inactivation). These data have major implications in the knowledge of the CD38 structure, especially with regard to the location of disulfide bridges and their accessibility. Potential consequences of the conformational plasticity of CD38 should also be considered in its physiological functions such as signalling. [source] Neuropathology, biochemistry, and biophysics of ,-synuclein aggregationJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Vladimir N. Uversky Abstract Aggregation of ,-synuclein, an abundant and conserved pre-synaptic brain protein, is implicated as a critical factor in several neurodegenerative diseases. These diseases, known as synucleinopathies, include Parkinson's disease, dementia with Lewy bodies (LBs), diffuse LB disease, the LB variant of Alzheimer's disease, multiple system atrophy, and neurodegeneration with brain iron accumulation type I. Although the precise nature of in vivo,-synuclein function remains elusive, considerable knowledge has been accumulated about its structural properties and conformational behavior. ,-Synuclein is a typical natively unfolded protein. It is characterized by the lack of rigid, well-defined, 3-D structure and possesses remarkable conformational plasticity. The structure of this protein depends dramatically on its environment and it accommodates a number of unrelated conformations. This paper provides an overview of the biochemistry, biophysics, and neuropathology of ,-synuclein aggregation. [source] A new crystal form of human tear lipocalin reveals high flexibility in the loop region and induced fit in the ligand cavityACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2009Daniel A. Breustedt Tear lipocalin (TLC) with the bound artificial ligand 1,4-butanediol has been crystallized in space group P21 with four protein molecules in the asymmetric unit and its X-ray structure has been solved at 2.6,Å resolution. TLC is a member of the lipocalin family that binds ligands with diverse chemical structures, such as fatty acids, phospholipids and cholesterol as well as microbial siderophores and the antibiotic rifampin. Previous X-ray structural analysis of apo TLC crystallized in space group C2 revealed a rather large bifurcated ligand pocket and a partially disordered loop region at the entrace to the cavity. Analysis of the P21 crystal form uncovered major conformational changes (i) in ,-strands B, C and D, (ii) in loops 1, 2 and 4 at the open end of the ,-barrel and (iii) in the extended C-terminal segment, which is attached to the ,-barrel via a disulfide bridge. The structural comparison indicates high conformational plasticity of the loop region as well as of deeper parts of the ligand pocket, thus allowing adaptation to ligands that differ vastly in size and shape. This illustrates a mechanism for promiscuity in ligand recognition which may also be relevant for some other physiologically important members of the lipocalin protein family. [source] A C-terminal segment of the V1R vasopressin receptor is unstructured in the crystal structure of its chimera with the maltose-binding proteinACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2005Syed Saad Mahmood The V1 vascular vasopressin receptor (V1R) is a G-protein-coupled receptor (GPCR) involved in the regulation of body-fluid osmolality, blood volume and blood pressure. Signal transduction is mediated by the third intracellular loop of this seven-transmembrane protein as well as by the C-terminal cytoplasmic segment. A chimera of the maltose-binding protein (MBP) and the C-terminal segment of V1R has been cloned, expressed, purified and crystallized. The crystals belong to space group P21, with unit-cell parameters a = 51.10, b = 66.56, c = 115.72,Å, , = 95.99°. The 1.8,Å crystal structure reveals the conformation of MBP and part of the linker region of this chimera, with the C-terminal segment being unstructured. This may reflect a conformational plasticity in the C-terminal segment that may be necessary for proper function of V1R. [source] | ||||||||||