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Structural Biology of Laminins
Essays in Biochemistry (2019) EBC20180075 https://doi.org/10.1042/EBC20180075 Review Article Structural biology of laminins Erhard Hohenester Department of Life Sciences, Imperial College London, London SW7 2AZ, U.K. Correspondence: Erhard Hohenester ([email protected]) Laminins are large cell-adhesive glycoproteins that are required for the formation and func- tion of basement membranes in all animals. Structural studies by electron microscopy in the early 1980s revealed a cross-shaped molecule, which subsequently was shown to con- sist of three distinct polypeptide chains. Crystallographic studies since the mid-1990s have added atomic detail to all parts of the laminin heterotrimer. The three short arms of the cross are made up of continuous arrays of disulphide-rich domains. The globular domains at the tips of the short arms mediate laminin polymerization; the surface regions involved in this process have been identified by structure-based mutagenesis. The long arm of the cross is an α-helical coiled coil of all three chains, terminating in a cell-adhesive globular region. The molecular basis of cell adhesion to laminins has been revealed by recent structures of heterotrimeric integrin-binding fragments and of a laminin fragment bound to the carbohy- drate modification of dystroglycan. The structural characterization of the laminin molecule is essentially complete, but we still have to find ways of imaging native laminin polymers at molecular resolution. Introduction About 40 years ago, two laboratories independently purified a large glycoprotein from the extracellular matrix produced by mouse tumour cells [1,2]. Antibodies raised against this glycoprotein reacted with basement membranes (also known as basal laminae) in mouse tissues, prompting Rupert Timpl and col- leagues to name the new protein laminin. -
Structural Insight Into Marburg Virus Nucleoprotein-RNA Complex Formation
bioRxiv preprint doi: https://doi.org/10.1101/2021.07.13.452116; this version posted July 13, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Structural insight into Marburg virus nucleoprotein-RNA complex formation 2 3 Yoko Fujita-Fujiharu1,2,3, Yukihiko Sugita1,2,4, Yuki Takamatsu1,#, Kazuya Houri1,2,3, Manabu 4 Igarashi5, Yukiko Muramoto1,2,3, Masahiro Nakano1,2,3, Yugo Tsunoda1, Stephan Becker6,7, 5 Takeshi Noda1,2,3* 6 7 1 Laboratory of Ultrastructural Virology, Institute for Frontier Life and Medical Sciences, 8 Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan 9 2 Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, 53 10 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan 11 3 CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332- 12 0012, Japan 13 4 Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan. 14 5 Division of Epidemiology, International Institute for Zoonosis Control, Hokkaido University, 15 Sapporo 001-0020, Japan 16 6 Institute of Virology, University of Marburg, 35043 Marburg, Germany. 17 7 German Center for Infection Research (DZIF), Marburg-Gießen-Langen Site, University of 18 Marburg, 35043 Marburg, Germany. 19 20 # present address: Department of Virology I, National Institute of Infectious Diseases, Gakuen 21 4-7-1, Musashimurayama-city, Tokyo 208-0011, Japan 22 *correspondence to: [email protected] 23 24 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.13.452116; this version posted July 13, 2021. -
Leucine Zippers
Leucine Zippers Leucine Zippers Advanced article Toshio Hakoshima, Nara Institute of Science and Technology, Nara, Japan Article contents Introduction The leucine zipper (ZIP) motif consists of a periodic repetition of a leucine residue at every Structural Basis of ZIP seventh position and forms an a-helical conformation, which facilitates dimerization and in Occurrence of ZIP and Coiled-coil Motifs some cases higher oligomerization of proteins. In many eukaryotic gene regulatory proteins, Dimerization Specificity of ZIP the ZIP motif is flanked at its N-terminus by a basic region containing characteristic residues DNA-binding Specificity of bZIP that facilitate DNA binding. doi: 10.1038/npg.els.0005049 Introduction protein modules for protein–protein interactions. Knowing the structure and function of these motifs A structure referred to as the leucine zipper or enables us to understand the molecular recognition simply as ZIP has been proposed to explain how a system in several biological processes. class of eukaryotic gene regulatory proteins works (Landschulz et al., 1988). A segment of the mammalian CCAAT/enhancer binding protein (C/EBP) of 30 Structural Basis of ZIP amino acids shares notable sequence similarity with a segment of the cellular Myc transforming protein. The The a helix is a secondary structure element that segments have been found to contain a periodic occurs frequently in proteins. Alpha helices are repetition of a leucine residue at every seventh stabilized in proteins by being packed into the position. A periodic array of at least four leucines hydrophobic core of a protein through hydrophobic has also been noted in the sequences of the Fos and side chains. -
Folding and Unfolding of Helix-Turn-Helix Motifs in the Gas Phase
FOCUS:FROM MOBILITIES TO PROTEOMES Folding and Unfolding of Helix-Turn-Helix Motifs in the Gas Phase Lloyd W. Zilch, David T. Kaleta, Motoya Kohtani, Ranjani Krishnan, and Martin F. Jarrold Department of Chemistry, Indiana University, Bloomington, Indiana, USA Ion mobility measurements and molecular dynamic simulations have been performed for a series of peptides designed to have helix-turn-helix motifs. For peptides with two helical ϩ ϩ ϩ ϩ sections linked by a short loop region: AcA14KG3A14K 2H , AcA14KG5A14K 2H , ϩ ϩ ϩ ϩ ϭ ϭ ϭ AcA14KG7A14K 2H , and AcA14KSar3A14K 2H (Ac acetyl, A alanine, G glycine, Sar ϭ sarcosine and K ϭ lysine); a coiled-coil geometry with two anti-parallel helices is the lowest energy conformation. The helices uncouple and the coiled-coil unfolds as the temperature is raised. Equilibrium constants determined as a function of temperature yield enthalpy and entropy changes for the unfolding of the coiled-coil. The enthalpy and entropy changes depend on the length and nature of the loop region. For a peptide with three helical sections: protonated AcA14KG3A14KG3A14K; a coiled-coil bundle with three helices side-by-side is substantially less stable than a geometry with two helices in an antiparallel coiled-coil and the third helix collinear with one of the other two. (J Am Soc Mass Spectrom 2007, 18, 1239–1248) © 2007 American Society for Mass Spectrometry ϩ ϩ he function and activity of a protein is controlled AcA15K H helices are remarkably stable in the gas by its conformation. The conformation is deter- phase, and have been shown to remain intact to over ϩ ϩ Tmined by the protein’s potential energy surface, 700 K. -
Stapled Peptides—A Useful Improvement for Peptide-Based Drugs
molecules Review Stapled Peptides—A Useful Improvement for Peptide-Based Drugs Mattia Moiola, Misal G. Memeo and Paolo Quadrelli * Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy; [email protected] (M.M.); [email protected] (M.G.M.) * Correspondence: [email protected]; Tel.: +39-0382-987315 Received: 30 July 2019; Accepted: 1 October 2019; Published: 10 October 2019 Abstract: Peptide-based drugs, despite being relegated as niche pharmaceuticals for years, are now capturing more and more attention from the scientific community. The main problem for these kinds of pharmacological compounds was the low degree of cellular uptake, which relegates the application of peptide-drugs to extracellular targets. In recent years, many new techniques have been developed in order to bypass the intrinsic problem of this kind of pharmaceuticals. One of these features is the use of stapled peptides. Stapled peptides consist of peptide chains that bring an external brace that force the peptide structure into an a-helical one. The cross-link is obtained by the linkage of the side chains of opportune-modified amino acids posed at the right distance inside the peptide chain. In this account, we report the main stapling methodologies currently employed or under development and the synthetic pathways involved in the amino acid modifications. Moreover, we report the results of two comparative studies upon different kinds of stapled-peptides, evaluating the properties given from each typology of staple to the target peptide and discussing the best choices for the use of this feature in peptide-drug synthesis. Keywords: stapled peptide; structurally constrained peptide; cellular uptake; helicity; peptide drugs 1. -
And Beta-Helical Protein Motifs
Soft Matter Mechanical Unfolding of Alpha- and Beta-helical Protein Motifs Journal: Soft Matter Manuscript ID SM-ART-10-2018-002046.R1 Article Type: Paper Date Submitted by the 28-Nov-2018 Author: Complete List of Authors: DeBenedictis, Elizabeth; Northwestern University Keten, Sinan; Northwestern University, Mechanical Engineering Page 1 of 10 Please doSoft not Matter adjust margins Soft Matter ARTICLE Mechanical Unfolding of Alpha- and Beta-helical Protein Motifs E. P. DeBenedictis and S. Keten* Received 24th September 2018, Alpha helices and beta sheets are the two most common secondary structure motifs in proteins. Beta-helical structures Accepted 00th January 20xx merge features of the two motifs, containing two or three beta-sheet faces connected by loops or turns in a single protein. Beta-helical structures form the basis of proteins with diverse mechanical functions such as bacterial adhesins, phage cell- DOI: 10.1039/x0xx00000x puncture devices, antifreeze proteins, and extracellular matrices. Alpha helices are commonly found in cellular and extracellular matrix components, whereas beta-helices such as curli fibrils are more common as bacterial and biofilm matrix www.rsc.org/ components. It is currently not known whether it may be advantageous to use one helical motif over the other for different structural and mechanical functions. To better understand the mechanical implications of using different helix motifs in networks, here we use Steered Molecular Dynamics (SMD) simulations to mechanically unfold multiple alpha- and beta- helical proteins at constant velocity at the single molecule scale. We focus on the energy dissipated during unfolding as a means of comparison between proteins and work normalized by protein characteristics (initial and final length, # H-bonds, # residues, etc.). -
Rapid and Accurate Prediction of Coiled-Coil Structures and Application to Modelling Intermediate filaments
bioRxiv preprint doi: https://doi.org/10.1101/123869; this version posted April 14, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. CCFold: rapid and accurate prediction of coiled-coil structures and application to modelling intermediate filaments Dmytro Guzenko and Sergei V. Strelkov ∗ Department of Pharmaceutical and Pharmacological Sciences KU Leuven, Leuven 3000, Belgium. ∗To whom correspondence should be addressed. Abstract Accurate molecular structure of the protein dimer representing the elementary building block of intermediate filaments (IFs) is essential towards the understanding of the filament assembly, rationalizing their mechanical properties and explaining the effect of disease- related IF mutations. The dimer contains a ∼300-residue long α-helical coiled coil which is not assessable to either direct experimental structure determination or modelling using standard approaches. At the same time, coiled coils are well-represented in structural databases. Here we present CCFold, a generally applicable threading-based algorithm which produces coiled-coil models from protein sequence only. The algorithm is based on a statistical analysis of experimentally determined structures and can handle any hydrophobic repeat patterns in addition to the most common heptads. We demonstrate that CCFold outperforms general-purpose computational folding in terms of accuracy, while being faster by orders of magnitude. By combining the CCFold algorithm and Rosetta folding we generate representative dimer models for all IF protein classes. The source code is freely available at https://github.com/biocryst/IF 1 Introduction Intermediate filaments (IFs) are an important example of a protein assembly based on α-helical coiled coils (CCs). -
The Generic Geometry of Helices and Their Close-Packed Structures
Theor Chem Acc (2010) 125:207–215 DOI 10.1007/s00214-009-0639-4 REGULAR ARTICLE The generic geometry of helices and their close-packed structures Kasper Olsen Æ Jakob Bohr Received: 23 May 2009 / Accepted: 9 September 2009 / Published online: 25 September 2009 Ó The Author(s) 2009. This article is published with open access at Springerlink.com Abstract The formation of helices is an ubiquitous 1 Introduction phenomenon for molecular structures whether they are biological, organic, or inorganic, in nature. Helical struc- Helical structures are common in chain molecules such as tures have geometrical constraints analogous to close- proteins, RNA, and DNA, e.g., a-helices and the A, B and Z packing of three-dimensional crystal structures. For helical forms of DNA. In this paper, we consider the packing of packing the geometrical constraints involve parameters idealized helices formed by a continuous tube with the such as the radius of the helical cylinder, the helical pitch purpose to calculate the constraints on such helices which angle, and the helical tube radius. In this communication, arise from close-packing and space filling considerations; the geometrical constraints for single helix, double helix, we consider single helical tubes, as well as sets of two and for double helices with minor and major grooves are identical helical tubes. It is found that the efficiency of the calculated. The results are compared with values from the use of space depends on the helical pitch angle, and the literature for helical polypeptide backbone structures, the optimum helical pitch angle is determined for single and a-, p-, 310-, and c-helices. -
Coiled- Coil-Forming Protein Domains
Proc. Natl. Acad. Sci. USA Vol. 92, pp. 3100-3104, April 1995 Biochemistry Stathmin interaction with a putative kinase and coiled-coil-forming protein domains (two-hybrid/regulatory cascades/BiP) ALEXANDRE MAUCUER*t, JACQUES H. CAMONISt, AND ANDRE' SOBEL* *Institut National de la Sante et de la Recherche Medicale, Unit6 153, 17 rue du Fer a Moulin, 75005 Paris, France; and tInstitut National de la Sante et de la Recherche Medicale, Unite 248, 10 Av. de Verdun, 75010 Paris, France Communicated by George A. Olah, University of Southern California, Los Angeles, CA, December 27, 1994 (received for review October 17, 1994) ABSTRACT Stathmin is a ubiquitous, cytosolic 19-kDa in all tissues, the highest level being in brain, where it is mostly protein, which is phosphorylated on up to four sites in present in neurons (21, 22), in testis (18), and in activated or response to many regulatory signals within cells. Its molecular leukemic lymphocytes (5, 23). On the basis of its overall characterization indicates a functional organization including regulatory and molecular features, we proposed that stathmin an N-terminal regulatory domain that bears the phosphory- could act as a general integrator and relay of signals controlling lation sites, linked to a putative a-helical binding domain cell proliferation, differentiation, and functions, during devel- predicted to participate in coiled-coil, protein-protein inter- opment and adult life (2, 24). actions. We therefore proposed that stathmin may play the Phosphorylation studies (25-27), sequence analysis (28-31), role of a relay integrating diverse intracellular regulatory interspecies comparisons (31), and circular dichroism (32) pathways; its action on various target proteins would be a indicate that stathmin is composed of (i) an N-terminal function of its combined phosphorylation state. -
A Seven-Helix Coiled Coil
A seven-helix coiled coil Jie Liu*, Qi Zheng*, Yiqun Deng*, Chao-Sheng Cheng*, Neville R. Kallenbach†, and Min Lu*‡ *Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021; and †Department of Chemistry, New York University, New York, NY 10003 Edited by Janet M. Thornton, European Bioinformatics Institute, Cambridge, United Kingdom, and approved August 28, 2006 (received for review June 12, 2006) Coiled-coil proteins contain a characteristic seven-residue se- and d residues. Interior packing of the side chains at the a and quence repeat whose positions are designated a to g. The inter- d positions, in fact, has been shown to dominate the global acting surface between ␣-helices in a classical coiled coil is formed architecture of coiled coils (23). Polar side chains at the a and by interspersing nonpolar side chains at the a and d positions with d positions also can destabilize coiled-coil structure yet impose hydrophilic residues at the flanking e and g positions. To explore a high degree of conformational selectivity (4, 24). Moreover, how the chemical nature of these core amino acids dictates the ionic interactions between the e and g residues have been shown overall coiled-coil architecture, we replaced all eight e and g to influence the specificity of coiled-coil assembly (10–18). For residues in the GCN4 leucine zipper with nonpolar alanine side example, repulsive or attractive interactions between the e and chains. Surprisingly, the alanine-containing mutant forms a stable g side chains can control the extent of homo- versus heterodimer- ␣-helical heptamer in aqueous solution. -
Breaking Non-Native Hydrophobic Clusters Is the Rate-Limiting Step In
Shibasish Chowdhury Wei Zhang Breaking Non-Native Chun Wu Guoming Xiong Hydrophobic Clusters is the Yong Duan Rate-Limiting Step in the Department of Chemistry and Biochemistry, Folding of an Alanine-Based Center of Biomedical Research Excellence, Peptide University of Delaware, Newark, DE 19716 Received 13 March 2002; accepted 29 April 2002 Abstract: The formation mechanism of an alanine-based peptide has been studied by all-atom molecular dynamics simulations with a recently developed all-atom point-charge force field and the Generalize Born continuum solvent model at an effective salt concentration of 0.2M. Thirty-two simulations were conducted. Each simulation was performed for 100 ns. A surprisingly complex folding process was observed. The development of the helical content can be divided into three phases with time constants of 0.06–0.08, 1.4–2.3, and 12–13 ns, respectively. Helices initiate extreme rapidly in the first phase similar to that estimated from explicit solvent simulations. Hydrophobic collapse also takes place in this phase. A folding intermediate state develops in the second phase and is unfolded to allow the peptide to reach the transition state in the third phase. The folding intermediate states are characterized by the two-turn short helices and the transition states are helix–turn–helix motifs—both of which are stabilized by hydrophobic clusters. The equilibrium helical content, calculated by both the main-chain ⌽–⌿ torsion angles and the main-chain hydrogen bonds, is 64–66%, which is in remarkable agreement with experiments. After corrected for the solvent viscosity effect, an extrapolated folding time of 16–20 ns is obtained that is in qualitative agreement with experiments. -
Human Leucine-Rich Repeat Proteins: a Genome-Wide Bioinformatic Categorization and Functional Analysis in Innate Immunity
Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity Aylwin C. Y. Nga,b,1, Jason M. Eisenberga,b,1, Robert J. W. Heatha, Alan Huetta, Cory M. Robinsonc, Gerard J. Nauc, and Ramnik J. Xaviera,b,2 aCenter for Computational and Integrative Biology, and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; bThe Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142; and cMicrobiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 Edited by Jeffrey I. Gordon, Washington University School of Medicine, St. Louis, MO, and approved June 11, 2010 (received for review February 17, 2010) In innate immune sensing, the detection of pathogen-associated proteins have been implicated in human diseases to date, notably molecular patterns by recognition receptors typically involve polymorphisms in NOD2 in Crohn disease (8, 9), CIITA in leucine-rich repeats (LRRs). We provide a categorization of 375 rheumatoid arthritis and multiple sclerosis (10), and TLR5 in human LRR-containing proteins, almost half of which lack other Legionnaire disease (11). identifiable functional domains. We clustered human LRR proteins Most LRR domains consist of a chain of between 2 and 45 by first assigning LRRs to LRR classes and then grouping the proteins LRRs (12). Each repeat in turn is typically 20 to 30 residues long based on these class assignments, revealing several of the resulting and can be divided into a highly conserved segment (HCS) fol- protein groups containing a large number of proteins with certain lowed by a variable segment (VS).