Read about some of the latest publications from the Department.
Structural basis of Latrophilin-FLRT interaction. Jackson VA, Del Toro D, Carrasquero M, Roversi P, Harlos K, Klein R and Seiradake E. Structure 2015 Feb 17
Latrophilin are adhesion type G-protein-coupled receptors with emerging functions in synapse development. The N-terminal region binds the endogenous cell adhesion molecule FLRT, a major regulator of cortical and synapse development. The researchers present crystallographic data revealing the Latrophilin olfactomedin-like domain forms a five-bladed β-propeller fold and that a conserved calcium-binding site is located at the centre of the protein. They also show that Latrophilin-FLRT binding depends on a conserved binding site and that mutations in this site inhibit Latrophilin-FLRT signaling. The findings give molecular insight into Latrophilin structure, its FLRT-binding mechanism, and a role for Latrophilin and FLRT that goes beyond a simply adhesive interaction.
Exploring the interaction of SV2A with racetams using homology modelling, molecular dynamics and site-directed mutagenesis. Lee J, Daniels V, Sands ZA, Lebon F, Shi J and Biggin PC. PLoS One 2015 Feb 18;10(2):e0116589
The putative Major Facilitator Superfamily (MFS) transporter, SV2A, is the target for levetiracetam (LEV), a successful anti-epileptic drug. However, the mode of action of LEV at the molecular level is not known. A better understanding would help in the design of improved anti-epileptic compounds. Since there is no structure for SV2A, homology modelling can provide insight into the ligand-binding site. In this paper, the group uses a sequence conservation analysis to help guide the homology modelling process and generate the models, which they assess further with Molecular Dynamics. They suggest additional residues that line the binding pocket and confirm these experimentally. The results shed light on the way LEV analogues may interact with SV2A and may help with the on-going design of improved anti-epileptic compounds.
The C.elegans TPR-containing protein, TRD-1, regulates cell fate choice in the developing germ line and epidermis. Hughes S, Wilkinson H, Gilbert SPR, Kishida M, Ding SS and Woollard A. PLoS One 2014; 9(12): e114998
Correct cell fate choice is crucial in development. In post-embryonic development of the hermaphroditic Caenorhabitis elegans, distinct cell fates must be adopted in two diverse tissues. In the germline, stem cells adopt one of three possible fates: mitotic cell cycle, or gamete formation via meiosis, producing either sperm or oocytes. In the epidermis, the stem cell-like seam cells divide asymmetrically, with the daughters taking on either a proliferative (seam) or differentiated (hypodermal or neuronal) fate. The researchers describe isolation of a novel conserved C. elegans tetratricopeptide repeat containing protein, TRD-1, which has homologs in other species including humans (TTC27). They show that trd-1 is a new player in both the somatic and germline cell fate determination machinery, suggestive of a molecular connection between the development of these two diverse tissues.
Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design. Crispin M and Doores KJ. Curr Opin Virology Volume 11, April 2015, p63-69
The surface of enveloped viruses can be extensively glycosylated. Glycans are added and processed by the host-cell during biosynthesis, with glycoproteins typically undergoing α-mannosidase processing and glycosyltransferase extension to form complex-type glycans. In envelope viruses, exceptions to this default pathway are common and lead to the presence of oligomannose-type glycan structures on the virion surface. In one extreme example, HIV-1 uses a high density of glycans to limit host antibody recognition of protein. However, the high density limits glycan processing and the resulting oligomannose structures can be recognised by broadly neutralising antibodies isolated from HIV-1 infected patients. This paper discusses how divergence from host-cell glycosylation can be targeted for vaccine design.
Identifying and quantifying radiation damage at the atomic level. Gerstel M, Deane CM and Garman EF. J Synchrotron Radiation (2015.) 22, 201-212
Radiation damage impedes macromolecular diffraction experiments. Alongside the well-known effects of global radiation damage, site-specific radiation damage affects data quality and the accuracy of biological conclusions about protein mechanism and function. In this paper, the researchers define and validate BDamage, a new atomic metric, to recognise protein regions susceptible to specific damage and to quantify the damage at these sites. By applying BDamage to a large set of known protein structures, they identify correlations between the rates of damage and various physicochemical parameters. They find that there is a consistent positive correlation between specific damage and solvent accessibility.
Meikin is a conserved regulator of meiosis-I-specific kinetochore function. Kim J, Ishiguro K, Nambu A, Akiyoshi B, Yokobayashi S, Kagami A, Ishiguro T, Pendas AM, Takeda N , Sakakibara Y, Kitajima TS, Tanno Y, Sakuno T and Watanabe Y. (2015) Nature 517, 466-471
The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Meiotic kinetochore factors have only been identified in budding and fission yeasts. These molecules and their functions are thought to have diverged earlier and a conserved mechanism for meiotic kinetochore regulation therefore remains elusive. In this paper, the researchers identify a meiosis-specific kinetochore factor in mouse that they call MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection. The group's work indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.
Isolation and SAR studies of bicyclic iminosugars from Castanospermum australe as glycosidase inhibitors. Kato A, Hirokami Y, Kinami K, Tsuji Y, Miyawaki S, Adachi I, Hollinshead J, Nash RJ, Kiappes JL, Zitzmann N, Cha JK, Molyneux RJ, Fleet GWJ and Asano N. Phyochemistry Vol 111, March 2015, p124-131
The alkaloid castanospermine has attracted special interest as a potent inhibitor of various glycosidases such as glycoprotein processing ER α-glucosidases and lysosomal α-glucosidase. The iminosugar was first isolated from the seeds of the Australian legume Castanospermum australe and has been investigated for the treatment of various diseases such as cancer, hepatitis C virus and lysosomal diseases. In this paper, the researchers report the isolation, structural determination, and glycosidase inhibitory activity of fourteen iminosugars from C.australe. They also perform side-by-side comparison between monocyclic and bicyclic iminosugars and determine the difference in inhibition potency and spectrum.
Cell Cycle Control by a Minimal Cdk Network. Gérard C, Tyson JJ, Coudreuse D and Novák, B. (2015) PLoS Comput Biol 11(2): e1004056. doi:10.1371/journal.pcbi.1004056.
In present-day eukaryotes, a complex network of interacting proteins, including members of the cyclin and cyclin-dependent protein kinase (Cdk) families, and the Anaphase Promoting Complex (APC), controls the cell division cycle. Successful progression through the cell cycle depends on precise, temporally ordered regulation of the functions of these proteins. Yet in fission yeast, a minimal Cdk network consisting of a single cyclin-Cdk fusion protein can control DNA synthesis and mitosis in a manner that is indistinguishable from wild type. To understand better the cell cycle regulatory network, the researchers built and analysed a mathematical model of the molecular interactions controlling the G1/S and G2/M transitions in these minimal cells. Their approach provides novel insights into the organisation and quantitative regulation of wild type cell cycle progression.
Mechanism of thiosulfate oxidation in the SoxA family of cysteine-ligated cytochromes. Grabarczyk DB, Chappell PE, Eisel B, Johnson S, Lea SM and Berks BC. J Biol Chem 2015 doi:10.1074/jbc.M114.618025
The haemoprotein TsdA catalyses the oxidation of two thiosulfate molecules to form tetrathionate. In this paper, the researchers probe the mechanism of TsdA using biochemical and structural methods. They find that the catalytic reaction proceeds via a cysteine-S-thiosulfonate intermediate formed on a cysteine ligand to the active site heme. TsdA provides a catalytic model for other members of the SoxA enzyme family.
And already covered on the website:
Composition, Formation, and Regulation of the Cytosolic C-ring, a Dynamic Component of the Type III Secretion Injectisome. Diepold A, Kudryashev M, Delalez NJ, Berry RM and Armitage JP. PLoS Biol 13(1): e1002039. doi:10.1371/journal.pbio. 1002039
Liang C-C, Zhan B, Yoshikawa Y, Haas W, Gygi SP and Cohn MA (2015). UHRF1 is a sensor for DNA interstrand crosslinks and recruits FANCD2 to initiate the Fanconi Anemia pathway. Cell Reports. doi: http://dx.doi.org/10.1016/jcelrep.2015.02.053
Fowler PW, Orwick-Rydmark M, Radestock S, Solcan N, Dijkman P, Lyons JA, Kwok J, Caffrey M, Watts A, Forrest LR and Newstead S. Gating topology of the proton coupled oligopeptide symporters. (2015) Structure 23 290-301
Nothing to Sneeze At: A Dynamic and Integrative Computational Model of an Influenza Virion. Reddy T, Shorthouse D, Parton DL, Jefferys E, Fowler PW, Chavent M, Baaden M and Sansom MSP. Structure (2015) http://www.cell.com/structure/abstract/S0969-2126(15)00032-5
1 April 2015