Folding and Stability of the Aquaglyceroporin Glpf: Implications for Human Aqua(Glycero)Porin Diseases
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Biochimica et Biophysica Acta 1848 (2015) 622–633 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamem Review Folding and stability of the aquaglyceroporin GlpF: Implications for human aqua(glycero)porin diseases Noreen Klein a, Jennifer Neumann a, Joe D. O'Neil b,DirkSchneidera,⁎ a Department of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, 55128 Mainz, Germany b Department of Chemistry, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada article info abstract Article history: Aquaporins are highly selective polytopic transmembrane channel proteins that facilitate the permeation of Received 12 September 2014 water across cellular membranes in a large diversity of organisms. Defects in aquaporin function are associated Received in revised form 12 November 2014 with common diseases, such as nephrogenic diabetes insipidus, congenital cataract and certain types of cancer. Accepted 14 November 2014 In general, aquaporins have a highly conserved structure; from prokaryotes to humans. The conserved structure, Available online 20 November 2014 together with structural dynamics and the structural framework for substrate selectivity is discussed. The folding Keywords: pathway of aquaporins has been a topic of several studies in recent years. These studies revealed that a conserved Aquaporin protein structure can be reached by following different folding pathways. Based on the available data, we suggest GlpF a complex folding pathway for aquaporins, starting from the insertion of individual helices up to the formation of Membrane protein the tetrameric aquaporin structure. The consequences of some known mutations in human aquaporin-encoding Protein activity genes, which most likely affect the folding and stability of human aquaporins, are discussed. Protein folding © 2014 Elsevier B.V. All rights reserved. Contents 1. Introduction:theaquaporinfamily.................................................... 622 2. Theconservedstructureofaqua(glycero)porins.............................................. 623 3. Substrate specificityandproteindynamics................................................. 624 4. Foldingofaquaporins.......................................................... 626 4.1. TheGlpFmonomerfoldsinmultiplestages............................................. 626 4.2. OligomerizationiscrucialfortheGlpFfunctionandstability..................................... 626 4.3. GlpFunfoldinginvolvesmultiplestructuraltransitions........................................ 627 4.4. FoldingofGlpFinmultiplesteps.................................................. 628 5. Mutationsaffectthestructureandfunctionofhumanaquaporins...................................... 628 5.1. Mutations in GxxxG-like motifs, which mediate tight helix–helixcontacts............................... 629 5.2. Insertionofpolarresiduesintransmembranedomains........................................ 630 5.3. Mutations at helix–helixinterfaces................................................. 630 6. Conclusionsandoutlook......................................................... 630 Acknowledgements............................................................. 630 References.................................................................. 630 – – Abbreviations: AQP0 12, aquaporins 0 12; ar/R, aromatic/arginine; CD, Circular 1. Introduction: the aquaporin family Dichroism; CPK, Corey, Pauling, Koltun space-filling models; DMPC, 1,2-dimyristoyl-sn- glycero-3-phosphocholine; EC, extracellular; ER, endoplasmic reticulum; ERAD, ER- associateddegradation;GlpF, glycerol facilitator; IC,intracellular;MD, molecular dynamics; Aquaporins are highly selective polytopic transmembrane (TM) MIM, Major IntrinsicProtein; PIP, Plasma Membrane Intrinsic Proteins; SF, Selectivity Filter; channel proteins with a molecular mass of 26–34 kDa, which facilitate TM, transmembrane; wt, wild-type water flux across cellular membranes in a large diversity of organisms ⁎ Corresponding author at: Johannes Gutenberg-Universität, Institut für Pharmazie und [1]. As the passive flux of water is driven by the osmotic gradient, aqua- Biochemie, Johann-Joachim-Becher-Weg 30, 55128 Mainz, Germany. Tel.: +49 6131/39 25833; fax: +49 6131/39 25348. porins play a crucial role for osmoregulation in many tissues [2].Defects E-mail address: [email protected] (D. Schneider). in human aquaporin functions are associated with common diseases, http://dx.doi.org/10.1016/j.bbamem.2014.11.015 0005-2736/© 2014 Elsevier B.V. All rights reserved. N. Klein et al. / Biochimica et Biophysica Acta 1848 (2015) 622–633 623 Table 1 [23], the oligomeric state of GlpF was the topic of many controversial Aqua(glycero)porins with solved structures. discussions during the past decade [24–28]. However, by now it is com- Protein name Organism Resolution PDB-file Reference monly accepted that GlpF forms stable tetramers, which are even highly stable in detergent solutions. AQP0 Bovine lens 2.24 Å 1YMG [114] AQP0 Ovis aries 3.0 Å 1SOR [118] Sheep lens AQP1 Homo sapiens rbc 3.8 Å 1FQY [146] 2. The conserved structure of aqua(glycero)porins AQP1 Bos taurus 2.20 Å 1J4N [40] AQP2 Homo sapiens 2.75 Å 4NEF [147] AQP4 Rattus norvegicus 3.2 Å 2D57 [148] In recent years, several structures of aquaporins have been solved, AQP4 Homo sapiens 1.8 Å 3GD8 [149] and crystal structures of 14 aquaporins and aquaglyceroporins from 9 AQP5 (HSAQP5) Homo sapiens 2.0 Å 3D9S [150] different organisms have been published with resolutions varying AQPM Methanothermobacter 1.68 Å 2F2B [151] between 0.88 Å and 3.8 Å (Table 1). Importantly, the overall structures marburgensis of all aqua(glycero)porins are essentially identical, regardless of the AQPZ Escherichia coli 2.5 Å 1RC2 [41] SOPIP2;1 Spinacia oleracea 2.10 Å 1Z98 [56] subfamily or the host organism. GLPF Escherichia coli 2.2 Å 1FX8 [23] An aqua(glycero)porin monomer consists of a total of six TM helices PFAQP Plasmodium falciparum 2.05 Å 3C02 [152] and two reentry loops, which both form a half-spanning helix (Fig. 1A). AQY1 Pischia pastoris 1.15 Å 2W2E [153] These half-TM helices, which both contain the highly conserved NPA motif at their individual N-termini, align lengthwise and in this way span the membrane with a helical structure. The eight helices together such as nephrogenic diabetes insipidus, congenital cataract and certain form a right-handed helix bundle with the channel pore in its center types of cancer [3–10]. Although selectively facilitating water flux across (Fig. 1B), and the overall structure of an aqua(glycero)porin monomer membranes is the major physiological function of aquaporins, some is reminiscent of an hourglass (Fig. 2A) [29]. In the following, we will family members are also permeable to other molecules, such as urea, ni- refer to the helices according to their consecutive number, including trate and silicon, to gases such as ammonia, carbon dioxide and nitrogen both half-spanning helices rather than numbering only the TM helices. dioxide and to metalloids, such as arsenic and antimony [1,11–14].Fur- All aquaporin monomers comprise two subdomains with 3.5 TM thermore, there is also evidence that the human aquaporin AQP1 is per- segments, each with the same tertiary fold but oriented in the mem- meable to gaseous CO2 [15], and the gas-conducting channel is brane at a 180° angle (Fig. 1A). The inverted repeat structure places postulated to form in the center of an AQP1 tetramer. both the N- and C-termini of the proteins in the cytoplasm [30] and is Aquaporins are categorized into three subfamilies, based on the a common theme among helical bundle membrane proteins [31].Itpro- conservation of the amino acids flanking two conserved amino acid vides the protein with an internal “quasi-symmetry” with a twofold motifs (NPA motifs) [16,17]. In humans, the classical aquaporins pseudo axis of rotation. This internal tandem repeat is conserved (AQP0, AQP1, AQP2, AQP4, AQP5, AQP6 and AQP8) are only permeable among all aqua(glycero)porins and probably reflects the evolution of to water, whereas members of the subfamily of aquaglyceroporins the aquaporins: during the course of evolution a primordial precursor (AQP3, AQP7, AQP9 and AQP10) are additionally permeable to glycerol gene likely coded for a protein with dual TM topology, and thus aquapo- and other small, polar solutes [13,17–19]. AQP11 and AQP12 are catego- rin precursor proteins were protein dimers [32]. After gene duplication, rized as “unorthodox aquaporins”, as they do not share a high sequence the individual subdomains evolved separately and eventually fused, identity around the conserved NPA motifs, as common for classical resulting in the aquaporin genes/proteins found today. Noteworthy, aquaporins and aquaglyceroporins (see below). Although AQP1, which although characteristic for all aqua(glycero)porins, there are further is found in erythrocyte membranes and various tissues including the proteins with an aquaporin fold, albeit they do not belong to the kidney, lung, vascular endothelium, brain and eye, was the first aquapo- aquaporin family. Prominent examples are the formate channel FocA rin to be characterized in 1992 [20–22], the glycerol facilitator GlpF [33–35] and the nitrite channel NirC [36]. of the bacterium Escherichia coli (E. coli) is thus far the best studied Like many other α-helical TM proteins, aquaporins assemble within member of the aquaporin family. GlpF has served as an experimentally biological membranes and form higher ordered oligomers.