Current Topics in Membranes is targeted toward scientists and researchers in biochemistry and molecular and cellular biology, providing the necessary membrane research to assist them in understanding the current state and future prospects of a particular field.
This volume on exchangers, in conjunction with a previous volume on cotransporters (volume 70), represents an up-to-date, systematic, and comprehensive review of all the major secondary active carrier proteins responsible for the absorption, secretion, and general transport of ions and solutes in mammalian organ systems and additional species. Each chapter is devoted to a specific transporter or a grouping of related transporters based on the well-recognized nomenclature of the SoLute Carrier (SLC) gene family. This book provides readers with the latest mechanistic information on the function and structure of specific transporters, as well as their history and physiological significance.
- Comprehensive review of all the major exchangers
- Emphasis on protein mechanism with the most recent findings from functional and structural work
- Authoritative work from experts in the field
Current Topics in Membranes is targeted toward scientists and researchers in biochemistry and molecular and cellular biology, providing the necessary membrane research to assist them in understanding the current state and future prospects of a particular field. This volume on exchangers, in conjunction with a previous volume on cotransporters (volume 70), represents an up-to-date, systematic, and comprehensive review of all the major secondary active carrier proteins responsible for the absorption, secretion, and general transport of ions and solutes in mammalian organ systems and additional species. Each chapter is devoted to a specific transporter or a grouping of related transporters based on the well-recognized nomenclature of the SoLute Carrier (SLC) gene family. This book provides readers with the latest mechanistic information on the function and structure of specific transporters, as well as their history and physiological significance. Comprehensive review of all the major exchangers Emphasis on protein mechanism with the most recent findings from functional and structural work Authoritative work from experts in the field
Structural Dynamics and Regulation of the Mammalian SLC9A Family of Na+/H+ Exchangers
Ruth Hendus-Altenburger*,†; Birthe B. Kragelund*; Stine Falsig Pedersen†,1 * Section for Biomolecular Sciences, Department of Biology, University of Copenhagen, Copenhagen, Denmark
† Section for Cell and Developmental Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
1 Corresponding author: sfpedersen@bio.ku.dk
Abstract
Mammalian Na+/H+ exchangers of the SLC9A family are widely expressed and involved in numerous essential physiological processes. Their primary function is to mediate the 1:1 exchange of Na+ for H+ across the membrane in which they reside, and they play central roles in regulation of body, cellular, and organellar pH. Their function is tightly regulated through mechanisms involving interactions with multiple protein and lipid-binding partners, phosphorylations, and other posttranslational modifications. Biochemical and mutational analyses indicate that the SLC9As have a short intracellular N-terminus, 12 transmembrane (TM) helices necessary and sufficient for ion transport, and a C-terminal cytoplasmic tail region with essential regulatory roles. No high-resolution structures of the SLC9As exist; however, models based on crystal structures of the bacterial NhaAs support the 12 TM organization and suggest that TMIV and XI may form a central part of the ion-translocation pathway, whereas pH sensing may involve TMII, TMIX, and several intracellular loops. Similar to most ion transporters studied, SLC9As likely exist as coupled dimers in the membrane, and this appears to be important for the well-studied cooperativity of H+ binding.
The aim of this work is to summarize and critically discuss the currently available evidence on the structural dynamics, regulation, and binding partner interactions of SLC9As, focusing in particular on the most widely studied isoform, SLC9A1/NHE1. Further, novel bioinformatic and structural analyses are provided that to some extent challenge the existing paradigm on how ions are transported by mammalian SLC9As.
Keywords
Na+/H+ exchanger
NHE1
NhaA
Acid–base transport, cellular pH regulation
Structure
Intrinsic disorder
Phosphorylation
Abbreviations
at Amphiuma tridactylum
CaM calmodulin
CaMKII calmodulin kinase II
CaN calcineurin
CHP calcineurin homologous protein
CK casein kinase
DAG diacylglycerol
EL extracellular loop
EM electron microscopy
ER endoplasmic reticulum
ERM ezrin, radixin, and moesin
FLIM fluorescence-lifetime imaging microscopy
FRET fluorescence resonance energy transfer
ID intrinsic disorder
IDPs intrinsically disordered proteins
IDR intrinsically disordered region
IFD interfacial domain
IL intracellular loop
IP immunoprecipitation
ITC ion-translocation center
ITD ion-translocation domain
LC liquid chromatography
LID lipid interaction domain
LPA lysophosphatitic acid
MAPK mitogen-activated protein kinase
Mj M. jannaschii
MS mass spectrometry
NHE Na+/H+ exchanger
NIK Ste-20 like Nck-interacting kinase
NMR nuclear magnetic resonance
NOE nuclear Overhauser effect
PDZ PSD-95/discs large/ZO-1
PE phorbol esters
PI(4,5)P2 phosphatidylinositol-4,5-bisphosphate
PKA protein kinase A
PKB protein kinase B
PKC protein kinase C
POT proton-dependent oliogopeptide transporter
PP1 protein phosphatase 1
RACK1 receptor for activated C kinase-1
SAXS small-angle X-ray scattering
SGK1 serum- and glucocorticoid-inducible kinase 1
SLC9A solute carrier 9A
TM transmembrane
Y2H yeast 2 hybrid
1 Introduction
The solute carrier 9A (SLC9A) family of mammalian Na+/H+ exchangers (NHEs) play essential roles in cellular, organellar, and systemic pH regulation, in cell volume regulation, and in vectorial ion transport, and consequently, in a wide array of physiological events depending on these processes (see Alexander & Grinstein, 2006; Boedtkjer, Bunch, & Pedersen, 2012; Burckhardt, Di Sole, & Helmle-Kolb, 2002; Donowitz, Ming, & Fuster, 2013; Orlowski & Grinstein, 2004, 2011). NHE dysregulation is associated with a rapidly growing list of pathophysiological conditions, of which some of the best studied are ischemia/reperfusion damage, cancer, diabetes, hypertension, epilepsy, and several gastrointestinal disorders (see Donowitz et al., 2013; Orlowski & Grinstein, 2011; Pedersen, O'Donnell, Anderson, & Cala, 2006). All the NHEs exhibit a membrane topology of a short intracellular N-terminus, 12 predicted transmembrane (TM) helices mediating ion translocation, and a C-terminal cytoplasmic tail region with essential roles in NHE posttranslational modification and interactions with binding partners (Boedtkjer et al., 2012; Donowitz et al., 2013; Orlowski & Grinstein, 2011; Shrode, Gan, D'Souza, Orlowski, & Grinstein, 1998; Wakabayashi, Pang, Su, & Shigekawa, 2000), Fig. 2.1.
In the solute carrier (SLC) nomenclature (http://slc.bioparadigms.org/), the mammalian NHEs were recently divided into SLC9A1–9 (NHE1–9), SLC9B1–B2 (NHA1–2), and SLC9C1 (Sperm-NHE), reflecting major sequence divergence between these three groups (see also Donowitz et al., 2013). While the physiology of many of the mammalian NHEs is relatively well understood, a comprehensive understanding of their structural and biophysical properties is lacking. Here, we summarize and discuss the current insight into the structural dynamics, regulation, and binding partner interactions of the mammalian NHEs, with particular focus on SLC9A1/NHE1 (which will be referred to as NHE1 throughout this work). Furthermore, we provide novel bioinformatic and structural analyses that to some extent challenge the existing paradigm on the mechanism of ion transport by mammalian NHEs, and point to new open questions in the understanding of their regulation.
2 Basic Functional Properties: Substrates, Driving Forces and Kinetics of SLC9As
SLC9A activity is...
Erscheint lt. Verlag | 15.4.2014 |
---|---|
Sprache | englisch |
Themenwelt | Studium ► 1. Studienabschnitt (Vorklinik) ► Physiologie |
Naturwissenschaften ► Biologie ► Biochemie | |
Naturwissenschaften ► Biologie ► Ökologie / Naturschutz | |
Naturwissenschaften ► Biologie ► Zellbiologie | |
Naturwissenschaften ► Biologie ► Zoologie | |
Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik | |
Technik | |
ISBN-10 | 0-12-800291-3 / 0128002913 |
ISBN-13 | 978-0-12-800291-9 / 9780128002919 |
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