Published by De Gruyter

Volume 392 Issue 1-2

Issue of Biological Chemistry

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Contents
Journal Overview

Publisher’s Note

June 18, 2011

Abstract

No abstract available

Guest Editorial

June 18, 2011

Highlight: Membrane transport in light of structure, function, and evolution

Robert Tampé, Enrico Schleiff

Page range: 3-3

Abstract

No abstract available

HIGHLIGHT: MEMBRANE TRANSPORT IN LIGHT OF STRUCTURE, FUNCTION, AND EVOLUTION

June 18, 2011

Pathways of transport protein evolution: recent advances

Vincent H. Lam, Jong-Hoon Lee, Abe Silverio, Henry Chan, Kenny M. Gomolplitinant, Tatyana L. Povolotsky, Ekaterina Orlova, Eric I. Sun, Carl H. Welliver, Milton H. Saier

Page range: 5-12

Abstract

We herein report recent advances in our understanding of transport protein evolution. Numerous families of complex transmembrane transport proteins are believed to have arisen from short channel-forming amphipathic or hydrophobic peptides by various types of intragenic duplication events. Distinct pathways distinguish families, demonstrating independent origins for some, and allowing assignment of others to superfamilies. Some families have diversified in topology, whereas others have remained uniform. An example of ‘retroevolution’ was discovered where a more complex carrier gave rise to a structurally and functionally simpler channel. The results described in this review article expand our understanding of protein evolution.

June 18, 2011

Evolution of YidC/Oxa1/Alb3 insertases: three independent gene duplications followed by functional specialization in bacteria, mitochondria and chloroplasts

Soledad Funes, Frank Kauff, Eli O. van der Sluis, Martin Ott, Johannes M. Herrmann

Page range: 13-19

Abstract

Members of the YidC/Oxa1/Alb3 protein family facilitate the insertion, folding and assembly of proteins of the inner membranes of bacteria and mitochondria and the thylakoid membrane of plastids. All homologs share a conserved hydrophobic core region comprising five transmembrane domains. On the basis of phylogenetic analyses, six subgroups of the family can be distinguished which presumably arose from three independent gene duplications followed by functional specialization. During evolution of bacteria, mitochondria and chloroplasts, subgroup-specific regions were added to the core domain to facilitate the association with ribosomes or other components contributing to the substrate spectrum of YidC/Oxa1/Alb3 proteins.

June 18, 2011

Omp85 in eukaryotic systems: one protein family with distinct functions

Enrico Schleiff, Uwe G. Maier, Thomas Becker

Page range: 21-27

Abstract

Omp85-like proteins are evolutionary ancient components of bacterial outer membranes and their evolutionary offspring. As a consequence, proteins of this family can be found in the outer membrane systems of Gram-negative bacteria and endosymbiotically derived organelles. In the different membranes, they perform distinct functions such as catalyzing protein insertion into or protein transport across the bilayer. Here, the knowledge on the Omp85-like proteins in the eukaryotic system with regard to structural properties and physiological behavior is summarized.

June 18, 2011

Evolution of ABC transporters by gene duplication and their role in human disease

Karobi Moitra, Michael Dean

Page range: 29-37

Abstract

The ATP-binding cassette (ABC) transporter genes represent the largest family of transporters and these genes are abundant in the genome of all vertebrates. Through analysis of the genome sequence databases we have characterized the full complement of ABC genes from several mammals and other vertebrates. Multiple gene duplication and deletion events were identified in ABC genes in different lineages indicating that the process of gene evolution is still ongoing. Gene duplication resulting in either gene birth or gene death plays a major role in the evolution of the vertebrate ABC genes. The understanding of this mechanism is important in the context of human health because these ABC genes are associated with human disease, involving nearly all organ systems of the body. In addition, ABC genes play an important role in the development of drug resistance in cancer cells. Future genetic, functional, and evolutionary studies of ABC transporters will provide important insight into human and animal biology.

June 18, 2011

A structural and functional analysis of type III periplasmic and substrate binding proteins: their role in bacterial siderophore and heme transport

Byron C.H. Chu, Hans J. Vogel

Page range: 39-52

Abstract

In Escherichia coli the Fhu, Fep and Fec transport systems are involved in the uptake of chelated ferric iron-siderophore complexes, whereas in pathogenic strains heme can also be used as an iron source. An essential step in these pathways is the movement of the ferric-siderophore complex or heme from the outer membrane transporter across the periplasm to the cognate cytoplasmic membrane ATP-dependent transporter. This is accomplished in each case by a dedicated periplasmic binding protein (PBP). Ferric-siderophore binding PBPs belong to the PBP protein superfamily and adopt a bilobal type III structural fold in which the two independently folded amino and carboxy terminal domains are linked together by a single long α-helix of approximately 20 amino acids. Recent structural studies reveal how the PBPs of the Fhu, Fep, Fec and Chu systems are able to bind their corresponding ligands. These complex structures will be discussed and placed in the context of our current understanding of the entire type III family of Gram-negative periplasmic binding proteins and related Gram-positive substrate binding proteins.

June 18, 2011

The multidrug transporter Pdr5: a molecular diode?

Rakeshkumar P. Gupta, Petra Kueppers, Lutz Schmitt, Robert Ernst

Page range: 53-60

Abstract

A subset of the family of ATP-binding cassette (ABC) transporters has been in focus owing to their involvement in conferring multidrug resistance in cancer cells and among immune compromised individuals. Saccharomyces cerevisiae is protected against xenobiotics by similar machineries that are part of the pleitropic drug resistance (PDR) network. The ABC transporter Pdr5 is an important member of this PDR network in yeast and is involved in cellular detoxification by the efflux of a wide variety of drugs and substrates. In this review, we focus on the aspects of detergent effects and the degeneracy in conserved sequences that is observed in the nucleotide binding domains of Pdr5 and discuss their functional relevance.

June 18, 2011

The lysosomal polypeptide transporter TAPL: more than a housekeeping factor?

Irina Bangert, Franz Tumulka, Rupert Abele

Page range: 61-66

Abstract

The transporter associated with antigen processing-like (TAPL) is a polypeptide transporter translocating cytosolic peptides into the lumen of lysosomes driven by ATP hydrolysis. TAPL belongs to the family of ABC transporters and forms a homodimer. This ABC transporter not only shows a broad tissue but also a wide phylogenetic distribution, because orthologs are still found in nematodes and insects. Here, we present the topology, substrate specificity, and distribution of this intracellular polypeptide transporter. Additionally, we will discuss its proposed physiological functions such as housekeeping together with a specialized factor for metabolite storage as well as for the adaptive immunity.

June 18, 2011

Pumping lipids with P4-ATPases

Rosa L. López-Marqués, Joost C.M. Holthuis, Thomas G. Pomorski

Page range: 67-76

Abstract

While accumulating evidence indicates that P4-ATPases catalyze phospholipid transport across cellular bilayers, their kinship to cation-pumping ATPases has raised fundamental questions concerning the underlying flippase mechanism. Loss of P4-ATPase function perturbs vesicle formation in late secretory and endocytic compartments. An intriguing concept is that P4-ATPases help drive vesicle budding by generating imbalances in transbilayer lipid numbers. Moreover, activation of P4-ATPases by phosphoinositides and other effectors of coat recruitment provide a potential mechanism to confine flippase activity to sites of vesicle biogenesis. These developments have raised considerable interest in understanding the mechanism, regulation and biological implications of P4-ATPase-catalyzed phospholipid transport.

June 18, 2011

Transporters, Trojan horses and therapeutics: suitability of bile acid and peptide transporters for drug delivery

Werner Kramer

Page range: 77-94

Abstract

Membrane transporters are major determinants for the pharmacokinetic, safety and efficacy behavior of drugs. Available technologies to study function and structure of transport proteins has strongly stimulated research in transporter biology and uncovered their importance for the drug discovery and development process, especially for drug absorption and disposition. Physiological transport systems are investigated as potential ferries to improve drug absorption and membrane permeation and to achieve organ-specific drug action. In particular, the bile acid transport systems in the liver and the small intestine and the oligopeptide transporters are of significant importance for molecular drug delivery.

June 18, 2011

Substrate recognition and translocation by polyspecific organic cation transporters

Hermann Koepsell

Page range: 95-101

Abstract

Organic cation transporters (OCTs) of the SLC22 family play a pivotal role in distribution and excretion of cationic drugs. They mediate electrogenic translocation of cations in both directions. OCTs are polyspecific transporters. During substrate translocation they perform a series of conformational changes involving an outward-facing conformation, an occluded state and an inward-facing conformation. Mutagenesis of OCT1 in combination with homology modeling showed that identical amino acids form the innermost parts of the outward-open and inward-open binding clefts. In addition to low affinity substrate binding sites, OCT1 contains high affinity substrate binding sites that can mediate inhibition via non-transported compounds.

June 18, 2011

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine

Thomas Steinkellner, Michael Freissmuth, Harald H. Sitte, Therese Montgomery

Page range: 103-115

Abstract

Amphetamine (‘Speed’), methamphetamine (‘Ice’) and its congener 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) are illicit drugs abused worldwide for their euphoric and stimulant effects. Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity.

June 18, 2011

SLC22 transporter family proteins as targets for cytostatic uptake into tumor cells

Shivangi Gupta, Gerhard Burckhardt, Yohannes Hagos

Page range: 117-124

Abstract

The response to chemotherapy by tumor cells depends on the concentration of cytostatics accumulated inside the cells. The accumulation of anticancer drugs in tumor cells is mainly dependent on functional expression of efflux and influx transporters and to a minor extent on passive diffusion through the membrane. Efflux transporters of the ABC family are partially responsible for the chemoresistance of cancer cells by secreting these cytostatics. Over the past decades, the role of ABC transporters in the chemoresistance of various malignant tumors has been very well documented. By contrast, very little is known about the impact on tumor therapy of influx transporters belonging to the solute carrier transporters (SLC family). In this review, we focus on the interaction of SLC22 transporters with cytostatics, the expression of these transporters in tumor cells as well as their impact on the chemosensitivity of cancer cells.

June 18, 2011

Role of the Ca²⁺-activated Cl^- channels bestrophin and anoctamin in epithelial cells

Karl Kunzelmann, Patthara Kongsuphol, Krongkarn Chootip, Caio Toledo, Joana R. Martins, Joana Almaca, Yuemin Tian, Ralph Witzgall, Jiraporn Ousingsawat, Rainer Schreiber

Page range: 125-134

Abstract

Two families of proteins, the bestrophins (Best) and the recently cloned TMEM16 proteins (anoctamin, Ano), recapitulate properties of Ca 2+ -activated Cl - currents. Best1 is strongly expressed in the retinal pigment epithelium and could have a function as a Ca 2+ -activated Cl - channel as well as a regulator of Ca 2+ signaling. It is also present at much lower levels in other cell types including epithelial cells, where it regulates plasma membrane localized Cl - channels by controlling intracellular Ca 2+ levels. Best1 interacts with important Ca 2+ -signaling proteins such as STIM1 and can interact directly with other Ca 2+ -activated Cl - channels such as TMEM16A. Best1 is detected in the endoplasmic reticulum (ER) where it shapes the dynamic ER structure and regulates cell proliferation, which could be important for renal cystogenesis. Ca 2+ -activated Cl - channels of the anoctamin family (TMEM16A) show biophysical and pharmacological properties that are typical for endogenous Ca 2+ -dependent Cl - channels. TMEM16 proteins are abundantly expressed and many reports demonstrate their physiological importance in epithelial as well as non-epithelial cells. These channels are also activated by cell swelling and can therefore control cell volume, proliferation and apoptosis. To fully understand the function and regulation of Ca 2+ -activated Cl - currents, it is necessary to appreciate that Best1 and TMEM16A are embedded in a protein network and that they probably operate in functional microdomains.

June 18, 2011

Single-molecule fluorescence resonance energy transfer techniques on rotary ATP synthases

Michael Börsch

Page range: 135-142

Abstract

Conformational changes of proteins can be monitored in real time by fluorescence resonance energy transfer (FRET). Two different fluorophores have to be attached to those protein domains which move during function. Distance fluctuations between the fluorophores are measured by relative fluorescence intensity changes or fluorescence lifetime changes. The rotary mechanics of the two motors of F o F 1 -ATP synthase have been studied in vitro by single-molecule FRET. The results are summarized and perspectives for other transport ATPases are discussed.

June 18, 2011

Structure determination of channel and transport proteins by high-resolution microscopy techniques

Marcel Meury, Daniel Harder, Zöhre Ucurum, Rajendra Boggavarapu, Jean-Marc Jeckelmann, Dimitrios Fotiadis

Page range: 143-150

Abstract

High-resolution microscopy techniques provide a plethora of information on biological structures from the cellular level down to the molecular level. In this review, we present the unique capabilities of transmission electron and atomic force microscopy to assess the structure, oligomeric state, function and dynamics of channel and transport proteins in their native environment, the lipid bilayer. Most importantly, membrane proteins can be visualized in the frozen-hydrated state and in buffer solution by cryo-transmission electron and atomic force microscopy, respectively. We also illustrate the potential of the scintillation proximity assay to study substrate binding of detergent-solubilized transporters prior to crystallization and structural characterization.

About this journal

Objective
Biological Chemistry keeps you up-to-date with all new developments in the molecular life sciences. In addition to original research reports, authoritative reviews written by leading researchers in the field keep you informed about the latest advances in the molecular life sciences. Rapid, yet rigorous reviewing ensures fast access to recent research results of exceptional significance in the biological sciences.

Topics

general biochemistry
pathobiochemistry
structural biology
molecular and cellular biology
genetics and epigenetics
molecular medicine
cancer research
virology
immunology
plant molecular biology and biochemistry
novel experimental methodologies

Article formats
Research Articles, Short Communications, Reviews and Minireviews
Reviews are published by invitation only, but suggestions to the Editor-in-Chief are welcome.

The journal is associated with the German Society for Biochemistry and Molecular Biology (GBM).

Volume 392 Issue 1-2

Issue of Biological Chemistry

Publisher’s Note

Abstract

Highlight: Membrane transport in light of structure, function, and evolution

Abstract

Pathways of transport protein evolution: recent advances

Abstract

Evolution of YidC/Oxa1/Alb3 insertases: three independent gene duplications followed by functional specialization in bacteria, mitochondria and chloroplasts

Abstract

Omp85 in eukaryotic systems: one protein family with distinct functions

Abstract

Evolution of ABC transporters by gene duplication and their role in human disease

Abstract

A structural and functional analysis of type III periplasmic and substrate binding proteins: their role in bacterial siderophore and heme transport

Abstract

The multidrug transporter Pdr5: a molecular diode?

Abstract

The lysosomal polypeptide transporter TAPL: more than a housekeeping factor?

Abstract

Pumping lipids with P4-ATPases

Abstract

Transporters, Trojan horses and therapeutics: suitability of bile acid and peptide transporters for drug delivery

Abstract

Substrate recognition and translocation by polyspecific organic cation transporters

Abstract

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine

Abstract

SLC22 transporter family proteins as targets for cytostatic uptake into tumor cells

Abstract

Role of the Ca2+-activated Cl- channels bestrophin and anoctamin in epithelial cells

Abstract

Single-molecule fluorescence resonance energy transfer techniques on rotary ATP synthases

Abstract

Structure determination of channel and transport proteins by high-resolution microscopy techniques

Abstract

Role of the Ca²⁺-activated Cl^- channels bestrophin and anoctamin in epithelial cells