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Molecular Markers of Serine Protease Evolution
The EMBO Journal Vol. 20 No. 12 pp. 3036±3045, 2001 Molecular markers of serine protease evolution Maxwell M.Krem and Enrico Di Cera1 ment and specialization of the catalytic architecture should correspond to signi®cant evolutionary transitions in the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box 8231, St Louis, history of protease clans. Evolutionary markers encoun- MO 63110-1093, USA tered in the sequences contributing to the catalytic apparatus would thus give an account of the history of 1Corresponding author e-mail: [email protected] an enzyme family or clan and provide for comparative analysis with other families and clans. Therefore, the use The evolutionary history of serine proteases can be of sequence markers associated with active site structure accounted for by highly conserved amino acids that generates a model for protease evolution with broad form crucial structural and chemical elements of applicability and potential for extension to other classes of the catalytic apparatus. These residues display non- enzymes. random dichotomies in either amino acid choice or The ®rst report of a sequence marker associated with serine codon usage and serve as discrete markers for active site chemistry was the observation that both AGY tracking changes in the active site environment and and TCN codons were used to encode active site serines in supporting structures. These markers categorize a variety of enzyme families (Brenner, 1988). Since serine proteases of the chymotrypsin-like, subtilisin- AGY®TCN interconversion is an uncommon event, it like and a/b-hydrolase fold clans according to phylo- was reasoned that enzymes within the same family genetic lineages, and indicate the relative ages and utilizing different active site codons belonged to different order of appearance of those lineages. -
B1–Proteases As Molecular Targets of Drug Development
Abstracts B1–Proteases as Molecular Targets of Drug Development B1-001 lin release from the beta cells. Furthermore, GLP-1 also stimu- DPP-IV structure and inhibitor design lates beta cell growth and insulin biosynthesis, inhibits glucagon H. B. Rasmussen1, S. Branner1, N. Wagtmann3, J. R. Bjelke1 and secretion, reduces free fatty acids and delays gastric emptying. A. B. Kanstrup2 GLP-1 has therefore been suggested as a potentially new treat- 1Protein Engineering, Novo Nordisk A/S, Bagsvaerd, Denmark, ment for type 2 diabetes. However, GLP-1 is very rapidly degra- 2Medicinal Chemistry, Novo Nordisk A/S, Maaloev, Denmark, ded in the bloodstream by the enzyme dipeptidyl peptidase IV 3Discovery Biology, Novo Nordisk A/S, Maaloev, DENMARK. (DPP-IV; EC 3.4.14.5). A very promising approach to harvest E-mail: [email protected] the beneficial effect of GLP-1 in the treatment of diabetes is to inhibit the DPP-IV enzyme, thereby enhancing the levels of The incretin hormones GLP-1 and GIP are released from the gut endogenously intact circulating GLP-1. The three dimensional during meals, and serve as enhancers of glucose stimulated insu- structure of human DPP-IV in complex with various inhibitors 138 Abstracts creates a better understanding of the specificity and selectivity of drug-like transition-state inhibitors but can be utilized for the this enzyme and allows for further exploration and design of new design of non-transition-state inhibitors that compete for sub- therapeutic inhibitors. The majority of the currently known DPP- strate binding. Besides carrying out proteolytic activity, the IV inhibitors consist of an alpha amino acid pyrrolidine core, to ectodomain of memapsin 2 also interacts with APP leading to which substituents have been added to optimize affinity, potency, the endocytosis of both proteins into the endosomes where APP enzyme selectivity, oral bioavailability, and duration of action. -
Gpi-Anchored Proteins in Reconstituted Lipid Bilayers
GPI-ANCHORED PROTEINS IN RECONSTITUTED LIPID BILAYERS: STRUCTURE, FUNCTION, AND CLEAVAGE BY PI-SPECFIC PHOSPHOLIPASE C A Thesis Presented to The Faculty of Graduate Studies of The University of Guelph by MARTY T. LEHTO In partial fulfilrnent of requirements for the degree of Doctor of Philosophy August 2001 O Marty T. Lehto, 2001 National Library Bibliothèque nationale 1+1 of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395. rue Wellington Ottawa ON Kt A ON4 Ottawa ON K1A ON4 Canada Canada Your file Votre r4f8me Our file Notre réfdrence The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant a la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, distribuer ou copies of this thesis in microfonq vendre des copies de cette thèse sous paper or electronic formats. la fome de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fkom it Ni la thèse ni des extraits substantiels May be printed or othenuise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. GPI-ANCHORED PROTEINS IN RECONSTITUTED LEPID BILAYERS: STRUCTURE, FUNCTION AND CLEAVAGE BY PI-SPECFIC PHOSPHOLPASE C Marty T. Lehto Advisor: University of Guelph, 200 1 Professor F.J. Sharom Many eukaryotic proteins are anchored to the ce11 surface by a glycosylphosphatidylinositol (GPI) moiety. -
Biased Signaling of G Protein Coupled Receptors (Gpcrs): Molecular Determinants of GPCR/Transducer Selectivity and Therapeutic Potential
Pharmacology & Therapeutics 200 (2019) 148–178 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential Mohammad Seyedabadi a,b, Mohammad Hossein Ghahremani c, Paul R. Albert d,⁎ a Department of Pharmacology, School of Medicine, Bushehr University of Medical Sciences, Iran b Education Development Center, Bushehr University of Medical Sciences, Iran c Department of Toxicology–Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Iran d Ottawa Hospital Research Institute, Neuroscience, University of Ottawa, Canada article info abstract Available online 8 May 2019 G protein coupled receptors (GPCRs) convey signals across membranes via interaction with G proteins. Origi- nally, an individual GPCR was thought to signal through one G protein family, comprising cognate G proteins Keywords: that mediate canonical receptor signaling. However, several deviations from canonical signaling pathways for GPCR GPCRs have been described. It is now clear that GPCRs can engage with multiple G proteins and the line between Gprotein cognate and non-cognate signaling is increasingly blurred. Furthermore, GPCRs couple to non-G protein trans- β-arrestin ducers, including β-arrestins or other scaffold proteins, to initiate additional signaling cascades. Selectivity Biased Signaling Receptor/transducer selectivity is dictated by agonist-induced receptor conformations as well as by collateral fac- Therapeutic Potential tors. In particular, ligands stabilize distinct receptor conformations to preferentially activate certain pathways, designated ‘biased signaling’. In this regard, receptor sequence alignment and mutagenesis have helped to iden- tify key receptor domains for receptor/transducer specificity. -
Bioinformatic Protein Family Characterisation
Linköping studies in science and technology Dissertation No. 1343 Bioinformatic protein family characterisation Joel Hedlund Department of Physics, Chemistry and Biology Linköping, 2010 1 The front cover shows a tree diagram of the relations between proteins in the MDR superfamily (papers III–IV), excluding non-eukaryotic sequences as well as four fifths of the remainder for clarity. In total, 518 out of the 16667 known members are shown, and 1.5 cm in the dendrogram represents 10 % sequence differences. The bottom bar diagram shows conservation in these sequences using the CScore algorithm from the MSAView program (papers II and V), with infrequent insertions omitted for brevity. This example illustrates the size and complexity of the MDR superfamily, and it also serves as an illuminating example of the intricacies of the field of bioinformatics as a whole, where, after scaling down and removing layer after layer of complexity, there is still always ample size and complexity left to go around. The back cover shows a schematic view of the three-dimensional structure of human class III alcohol dehydrogenase, indicating the positions of the zinc ion and NAD cofactors, as well as the Rossmann fold cofactor binding domain (red) and the GroES-like folding core of the catalytic domain (green). This thesis was typeset using LYX. Inkscape was used for figure layout. During the course of research underlying this thesis, Joel Hedlund was enrolled in Forum Scientium, a multidisciplinary doctoral programme at Linköping University, Sweden. Copyright © 2010 Joel Hedlund, unless otherwise noted. All rights reserved. Joel Hedlund Bioinformatic protein family characterisation ISBN: 978-91-7393-297-4 ISSN: 0345-7524 Linköping studies in science and technology, dissertation No. -
Protein Structure and Function from Sequence to Function (I)
BCHS 6229 ProteinProtein StructureStructure andand FunctionFunction Lecture 6 (Oct 27, 2011) From Sequence to Function (I): - Protein Profiling - Case Studies in Structural & Functional Genomics 1 From Sequence to Function in the age of Genomics How to predict functions for 1000s proteins? 1. “Conventional” sequence pattern 2. “Fold similarity - Structural genomics 3. Clustering microarray experiments 4. Data integration 2 From Sequence to Function in the age of Genomics •Genomics is making an increasing contribution to the study of protein structure function. •Sequence and structural comparison can usually give only limited information, however, and comprehensively characterizing the protein function of an uncharacterized protein in a cell or organism will always require additional experimental investigations on the purified proteins in vitro as well as cell biological and mutational studies in vivo. 3 From Sequence to Function in the age of Genomics •Proteomics Understand Proteins, through analyzing populations Structure (motions, packing,folds) Function Evolution Integration of information Structures - Sequences - Microarrays 4 Regulation of flagellar genes in C. jejuni Carrillo CD et al. J Biol Chem (2004) 279(19):20327-38. 5 Time and distance scales in functional genomics Time Process Example System Example Detection Methods Distance Interdisciplinary approaches are essential to determine the functions of gene products. 6 Sequence alignment and comparison General principle of alignments: Two homologous sequences derived from the same ancestral sequence will have at least some identical residues at the corresponding positions in the sequence; if corresponding positions in the sequence are aligned, the degree of matching should be statistically significant compared with that of two randomly chosen unrelated sequences. -
Shedding and Uptake of Gangliosides and Glycosylphosphatidylinositol-Anchored Proteins ⁎ Gordan Lauc A,B, , Marija Heffer-Lauc C
Biochimica et Biophysica Acta 1760 (2006) 584–602 http://www.elsevier.com/locate/bba Review Shedding and uptake of gangliosides and glycosylphosphatidylinositol-anchored proteins ⁎ Gordan Lauc a,b, , Marija Heffer-Lauc c a Department of Chemistry and Biochemistry, University of Osijek School of Medicine, J. Huttlera 4, 31000 Osijek, Croatia b Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, 10000 Zagreb, Croatia c Department of Biology, University of Osijek School of Medicine, J. Huttlera 4, 31000 Osijek, Croatia Received 30 September 2005; received in revised form 22 November 2005; accepted 23 November 2005 Available online 20 December 2005 Abstract Gangliosides and glycosylphosphatidylinositol (GPI)-anchored proteins have very different biosynthetic origin, but they have one thing in common: they are both comprised of a relatively large hydrophilic moiety tethered to a membrane by a relatively small lipid tail. Both gangliosides and GPI-anchored proteins can be actively shed from the membrane of one cell and taken up by other cells by insertion of their lipid anchors into the cell membrane. The process of shedding and uptake of gangliosides and GPI-anchored proteins has been independently discovered in several disciplines during the last few decades, but these discoveries were largely ignored by people working in other areas of science. By bringing together results from these, sometimes very distant disciplines, in this review, we give an overview of current knowledge about shedding and uptake of gangliosides and GPI-anchored proteins. Tumor cells and some pathogens apparently misuse this process for their own advantage, but its real physiological functions remain to be discovered. -
Molecular Characterization, Protein–Protein Interaction Network, and Evolution of Four Glutathione Peroxidases from Tetrahymena Thermophila
antioxidants Article Molecular Characterization, Protein–Protein Interaction Network, and Evolution of Four Glutathione Peroxidases from Tetrahymena thermophila Diana Ferro 1,2, Rigers Bakiu 3 , Sandra Pucciarelli 4, Cristina Miceli 4 , Adriana Vallesi 4 , Paola Irato 5 and Gianfranco Santovito 5,* 1 BIO5 Institute, University of Arizona, Tucson, AZ 85719, USA; [email protected] 2 Department of Pediatrics, Children’s Mercy Hospital and Clinics, Kansas City, MO 64108, USA 3 Department of Aquaculture and Fisheries, Agricultural University of Tirana, 1000 Tiranë, Albania; [email protected] 4 School of Biosciences and Veterinary Medicine, University of Camerino, 62032 Camerino, Italy; [email protected] (S.P.); [email protected] (C.M.); [email protected] (A.V.) 5 Department of Biology, University of Padova, 35131 Padova, Italy; [email protected] * Correspondence: [email protected] Received: 6 September 2020; Accepted: 1 October 2020; Published: 2 October 2020 Abstract: Glutathione peroxidases (GPxs) form a broad family of antioxidant proteins essential for maintaining redox homeostasis in eukaryotic cells. In this study, we used an integrative approach that combines bioinformatics, molecular biology, and biochemistry to investigate the role of GPxs in reactive oxygen species detoxification in the unicellular eukaryotic model organism Tetrahymena thermophila. Both phylogenetic and mechanistic empirical model analyses provided indications about the evolutionary relationships among the GPXs of Tetrahymena and the orthologous enzymes of phylogenetically related species. In-silico gene characterization and text mining were used to predict the functional relationships between GPxs and other physiologically-relevant processes. The GPx genes contain conserved transcriptional regulatory elements in the promoter region, which suggest that transcription is under tight control of specialized signaling pathways. -
A Modular Effector with a Dnase Domain and a Marker for T6SS Substrates
ARTICLE https://doi.org/10.1038/s41467-019-11546-6 OPEN A modular effector with a DNase domain and a marker for T6SS substrates Biswanath Jana1,3, Chaya M. Fridman1,3, Eran Bosis 2 & Dor Salomon 1 Bacteria deliver toxic effectors via type VI secretion systems (T6SSs) to dominate compe- titors, but the identity and function of many effectors remain unknown. Here we identify a Vibrio antibacterial T6SS effector that contains a previously undescribed, widespread DNase 1234567890():,; toxin domain that we call PoNe (Polymorphic Nuclease effector). PoNe belongs to a diverse superfamily of PD-(D/E)xK phosphodiesterases, and is associated with several toxin delivery systems including type V, type VI, and type VII. PoNe toxicity is antagonized by cognate immunity proteins (PoNi) containing DUF1911 and DUF1910 domains. In addition to PoNe, the effector contains a domain of unknown function (FIX domain) that is also found N-terminal to known toxin domains and is genetically and functionally linked to T6SS. FIX sequences can be used to identify T6SS effector candidates with potentially novel toxin domains. Our findings underline the modular nature of bacterial effectors harboring delivery or marker domains, specific to a secretion system, fused to interchangeable toxins. 1 Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel. 2 Department of Biotechnology Engineering, ORT Braude College of Engineering, 2161002 Karmiel, Israel. 3These authors contributed equally: Biswanath Jana, Chaya M. Fridman. Correspondence and requests for materials should be addressed to E.B. (email: [email protected]) or to D.S. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:3595 | https://doi.org/10.1038/s41467-019-11546-6 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-11546-6 acteria are social organisms that constantly interact with Vibrio parahaemolyticus 12-297/B does not encode MIX effectors, neighboring cells. -
The Role of G Protein-Coupled Receptor Kinases in Cancer Shan Yu1, Litao Sun2, Yufei Jiao3, Leo Tsz on Lee1
Int. J. Biol. Sci. 2018, Vol. 14 189 Ivyspring International Publisher International Journal of Biological Sciences 2018; 14(2): 189-203. doi: 10.7150/ijbs.22896 Review The Role of G Protein-coupled Receptor Kinases in Cancer Shan Yu1, Litao Sun2, Yufei Jiao3, Leo Tsz On Lee1 1. Centre of Reproduction Development and Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau 2. Department of Ultrasound, The Secondary Affiliated Hospital of Harbin Medical University, Harbin, China 3. Department of Pathology, The Secondary Affiliated Hospital of Harbin Medical University, Harbin, China Corresponding author: Leo T.O. Lee, Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China; E-mail: [email protected] © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2017.09.19; Accepted: 2017.11.17; Published: 2018.02.05 Abstract G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. Emerging evidence demonstrates that signaling through GPCRs affects numerous aspects of cancer biology such as vascular remolding, invasion, and migration. Therefore, development of GPCR-targeted drugs could provide a new therapeutic strategy to treating a variety of cancers. G protein-coupled receptor kinases (GRKs) modulate GPCR signaling by interacting with the ligand-activated GPCR and phosphorylating its intracellular domain. This phosphorylation initiates receptor desensitization and internalization, which inhibits downstream signaling pathways related to cancer progression. GRKs can also regulate non-GPCR substrates, resulting in the modulation of a different set of pathophysiological pathways. -
Progress in Lipid Research Progress in Lipid Research 46 (2007) 297–314 Review Non-Vesicular Sterol Transport in Cells
Progress in Lipid Research Progress in Lipid Research 46 (2007) 297–314 www.elsevier.com/locate/plipres Review Non-vesicular sterol transport in cells William A. Prinz * Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA Abstract Sterols such as cholesterol are important components of cellular membranes. They are not uniformly distributed among organelles and maintaining the proper distribution of sterols is critical for many cellular functions. Both vesicular and non- vesicular pathways move sterols between membranes and into and out of cells. There is growing evidence that a number of non-vesicular transport pathways operate in cells and, in the past few years, a number of proteins have been proposed to facilitate this transfer. Some are soluble sterol transfer proteins that may move sterol between membranes. Others are inte- gral membranes proteins that mediate sterol efflux, uptake from cells, and perhaps intracellular sterol transfer as well. In most cases, the mechanisms and regulation of these proteins remains poorly understood. This review summarizes our cur- rent knowledge of these proteins and how they could contribute to intracellular sterol trafficking and distribution. Published by Elsevier Ltd. Keywords: Cholestrol; Transport; Non-vesicular; Membranes; Lipid transport proteins Contents 1. Introduction ...................................................................... 298 2. Non-vesicular sterol transport pathways .................................................. 299 2.1. Transfer of cholesterol to the outer and inner mitochondrial membranes . .................... 300 2.2. PM to ERC sterol transport . ........................................................ 300 2.3. Sterol movement to and from lipid droplets (LDs). ........................................ 300 2.4. -
Functional Evolution Within a Protein Superfamily
This is a preprint of an article accepted for publication in Proteins, © copyright 2005. Functional Evolution within a Protein Superfamily Research Article Zhengping Yi, ‡,# Olga Vitek, @ M. A. Qasim, ‡ Stephen M. Lu, ‡,& Wuyuan Lu, ‡, § Michael Ranjbar, ‡ Jiangtian Li,~ Michael C. Laskowski,% Chris Bailey-Kellogg, ^,* and Michael Laskowski, Jr. ‡ Departments of ‡ Chemistry, @ Statistics, ~ Industrial Engineering, and ^ Computer Sciences, Purdue University, West Lafayette, IN 47907-2038 % Department of Mathematics, University of Maryland Current Addresses: #School of Life Sciences, Mail Code 4501, Arizona State University, University Drive and Mill Avenue, Tempe, AZ 85287. [email protected]; & Ventria Bioscience, 4110 N. Freeway Blvd., Sacramento, CA 95834; § Institute of Human Virology, University of Maryland, Baltimore, MD 21201 * To whom correspondence should be addressed: Chris Bailey-Kellogg, 6211 Sudikoff Laboratory, Department of Computer Science, Dartmouth College, Hanover, NH 03755, USA. Phone: 603-646-3385. Fax: 603-646-1672. Email: [email protected]. Key words: functional evolution, protein superfamilies, functional conservation, sequence hypervariability, specificity, protein-protein interactions Running head: Functional Evolution within a Protein Superfamily Abbreviations used: CHYM bovine chymotrypsin A PPE porcine pancreatic elastase CARL subtilisin Carlsberg HLE human leukocyte elastase SGPA Streptomyces griseus proteinase A SGPB Streptomyces griseus proteinase B SRA Sequence to Reactivity Algorithm OM1 avian ovomucoid