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The Arrangement of the Transmembrane Helices in The View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS 18694 FEBS Letters 409 (1997) 431-436 The arrangement of the transmembrane helices in the secretin receptor family of G-protein-coupled receptors Dan Donnelly* Department of Pharmacology, University of Leeds, Leeds LS2 9JT, UK Received 2 April 1997; revised version received 25 April 1997 ison with those based upon rhodopsin [2]. Furthermore, the Abstract The members of the secretin receptor family of G- protein-coupled receptors share no significant sequence similarity paucity of experimental data relating to the structure of SecR to the more familiar rhodopsin-like family. However, multiple family GPCRs means that automated modelling procedures sequence alignment analysis reveals seven hydrophobic regions using experimentally derived distance constraints are inappro- with significant a-helical periodicity. Residues that are likely to priate [16]. This paper describes the analysis of a multiple be buried on the interior of the helical bundle and others that are sequence alignment of members of the SecR family which likely to contact the lipid bilayer are identified. A predicted has enabled a prediction of the global arrangement of the arrangement of the helical bundle is described in which, by helix bundle and the positioning of individual residues within comparison with the arrangement in the rhodopsin family, helices this domain. Since the number of structure/function studies of 2 and 7 are more buried within the bundle while helix 3 is more this family of receptors is increasing rapidly, the models pre- exposed to the lipid bilayer. sented here will be useful for the planning of experiments, © 1997 Federation of European Biochemical Societies. especially those which require knowledge of the contact points between transmembrane helices. Key words: G-protein-coupled receptor; Secretm; Rhodopsin; Periodicity; Model; a-Helix 2. Methods Members of the SecR family were identified using the PRINTS 1. Introduction database [17] and complete sequences were extracted from the OWL sequence database v28.0 [18]. Sequence alignments were carried out using the program MALIGN [19] and trees were constructed using The investigation of the structure and function of G-pro- PHYLIP [20] with distances calculated as — 100(log[percentage iden- tein-coupled receptors (GPCR) has been the subject of numer- tity]/100). Fourier transform analysis was carried out using the com- ous studies over the past decade [1-5]. However, the vast puter programs within PERSCAN v7.0 as described previously [21]. majority of this work has concentrated upon the rhodopsin- The sequence alignment was scanned with a window of 18 residues using PERSCAN and the window with the highest a-helical perio- like GPCRs and, in particular, the ß2-adrenergic receptor and dicity (AP value [21]) within each hydrophobic region was defined as a rhodopsin itself. Significant advances in the elucidation of the transmembrane region. Note that if any sequences are identical within 3-dimensional structure of rhodopsin have been made in re- the window used in the PERSCAN analysis, the computer program cent years which have, in addition to multiple sequence align- only includes one such sequence in order to avoid bias. The sequence pattern at each position in each alignment was used to estimate the ment analysis and indirect structural studies, provided a pre- extent to which that position is buried or lipid-accessible, based upon liminary picture of the arrangement of the helices in the substitution tables calculated from alignments of proteins of known transmembrane bundle [6-11]. structure as described previously [21]. The periodicity in the predicted The receptors of the rhodopsin family are characterised by accessibilities was then calculated using a Fourier transform proce- dure to yield both an estimation of the extent of the a-helical perio- a number of highly conserved regions, or fingerprints, that can dicity (APmax) and a predicted direction of the internal face of the be used to align sequences that would otherwise be too diver- helix (0m„) relative to the first residue in that helix. gent for meaningful comparison [12]. However, the cloning of The SecR family sequences were grouped into either five major the secretin receptor and a variety of related GPCRs sug- groups or 15 smaller subsets of closely related receptors based upon gested a distinct GPCR family (the SecR family) that did the clustering in the dendrogram (Fig. 1). A buried position is defined where either (i) a residue (other than glycine or proline) is completely not match the rhodopsin family fingerprint [13,14]. Since these conserved over three of the five major groups or (ii) at least one receptors possess the seven putative transmembrane oc-helices charged residue (Asp, Glu, His, Lys or Arg) exists within the central that characterise GPCRs, it is reasonable to assume that the ten residues of the helix. A position is defined as being lipid accessible general fold of the transmembrane bundle in the two families if it is variable within one of the 15 smaller subsets of closely related is likely to be conserved. However, the absence of significant receptors. A variable position is defined as one where, for at least one of the smaller subsets, all the residues do not fall into one of the sequence identity allows for the possibility of significant following nine residue groupings: (A, L, V, I, M), (L, V, I, M, F), movements between the relative positions of equivalent a-heli- (F, Y, W, H), (A, G, P, S, T), (S, T, C), (N, Q, H), (S, T, N, Q), ces, as has been observed in the globin family [15]. In addi- (H, R, K), (D, E, N, Q). tion, the absence of a reliable sequence alignment of the two families means that the deduced internal faces of the helices 3. Results and discussion and the construction of molecular models of the SecR family must be deduced from first principles, rather than by compar- The Fourier transform analysis of the transmembrane se- quence alignments are summarised in Table 1. A value of *Fax: (44) 113-233-4331. APmax greater than 2 suggests that the a-helical periodicity E-mail: [email protected] is significant [21,22]. As can be seen from Table 1, all the 0014-5793/97/S17.00 © 1997 Federation of European Biochemical Societies. All rights reserved. P//S0014-5793(97)00546-2 432 D. DonnellylFEBS Letters 409 (1997) 431^36 DIHR MANSE DIURETIC HORMONE RECEPTOR CHKCRFR CRFR HUMAN CORTICOTROPIN RELEASING CRFR MOUSE FACTOR RECEPTORS \ CRFR RAT GRFR HUMAN A45367 GRFR PIG SSU4943S GROWTH-HORMONE RELEASING- GRFR MOUSE HORMONE RECEPTORS GRFR RAT ^ S29754 S CRC RAT HSU13989 SECRETIN RECEPTORS SCRC HUMAN HSU28281 VIPR RAT SSU49434 VASOACTIVE INTESTINAL \i VIPR HUMAN POLYPEPTIDE 1 RECEPTORS JC2195 VIPS HUMAN H HSVIP2R VASOACTIVE INTESTINAL VIPS MOUSE POLYPEPTIDE 2 RECEPTORS -C VIPS RAT S47631 rC PACR HUMAN S33449 PACAP RECEPTORS PACR RAT i A48204 GLPR RAT U01104 S45707 GLP-1 RECEPTORS GLPR HUMAN HSU10037 S79852 GIPR HUMAN HSGDIPR GASTRIC INHIBITORY GIPR MESAU POLYPEPTIDE RECEPTORS GIPR RAT GLR HUMAN GLR RAT GLUCAGON RECEPTORS JC4363 PTR2 HUMAN PTRR DIDMA PTRR RAT PTRR MOUSE PARATHYROID HORMONE MUSPTHR06 RECEPTORS PTRR HUMAN HI SSU18315 MMU18542 CLRB RAT CLRA RAT RATCR1B RATCR CALR HUMAN CALCITONIN RECEPTORS S44209 CALR PIG SSCALC1AB1 JC2477 RNCLR Fig. 1. Dendrogram depicting the clustering of the SecR family GPCRs based upon their relative levels of sequence identity. APmax values are greater or equal to 3.38 which suggests that was required, alongside the projection map of rhodopsin, to all seven of the hydrophobic regions in the SecR family form predict the extent to which each helix was buried within the transmembrane a-helices. helix bundle [7]. In the latter analysis, Baldwin used a large The Fourier transform analysis predicts the direction of the sequence alignment of rhodopsin-like GPCRs to predict internal face of each helix (Table 1) but it does not estimate whether individual residue positions on a helix were buried the extent of the buried face. For example, although a Fourier or lipid-accessible, which in turn allowed the extent of the transform analysis of the rhodopsin-like GPCRs was able to exposure of the entire helix to be estimated. It was then pos- show significant a-helical periodicity and predict the internal sible to assign each helix to a peak in the projection map of face of each helix [23], a more detailed analysis of the family rhodopsin. D. DonnellylFEBS Letters 409 (1997) 431^36 433 Fig. 2. Sequence alignment of the 7 putative transmembrane regions of the SecR family of GPCRs. Bold horizontal lines separate the 5 major clusters, while dotted horizontal lines separate the 15 smaller groups of closely related sequences. White letters upon black backgrounds repre- sent residue positions predicted to be buried. Boxed letters represent residue positions predicted to be lipid-accessible. The consensus prediction is shown on the final row with buried positions depicted with black squares and lipid-accessible residues depicted with asterisks (*). Conserved Gly and Pro residues are shown in bold. In order to predict the arrangement of the helices in the The dendrogram calculated from the full sequence align- SecR family of GPCRs, a similar procedure was used to com- ment of the SecR family is shown in Fig. 1. The clustering plement the Fourier transform analysis. The rules for defining pattern allows for the division of the SecR sequences into five whether a residue was either buried or in contact with the major categories (at approximately the 45% identity level) or bilayer were based upon general principles of protein structure else into 15 smaller subsets (at approximately the 75% identity as determined from a variety of studies [e.g.
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