Helical bundles

Sequence conservation is, in general, much weaker than structural conservation. There are proteins, which are clearly not related in sequence but are closely related in 3D-stmcture and fold, like heamoglobin and myoglobin, which have similar functions. In many proteins, fold elements like 4-helical bundles are repeated. Classifications of known structural folds of proteins are organized in the SCOP or CATH database see e.g., http //scop.mrc-lmb.cam.ac.uk/scop/. 

G-Protein-Coupled Receptors Are Seven-Helical Bundle Proteins Embedded in the... 

G-PROTEIN-COUPLED RECEPTORS ARE SEVEN-HELICAL BUNDLE PROTEINS EMBEDDED IN THE CELL MEMBRANE... 

Most of the G-protein-coupled receptors are homologous with rhodopsin however, other quantitatively minor families as well as some individual receptors do not share any of the structural features common to the rhodopsin family (Figure 2.3). The most dominant of these are the glucagon/VIP/caldtonin receptor family, or family B (which has approximately 65 members), and the metabotropic glutamate receptor family, or family C (which has approximately 15 members), as well as the frizzled/smoothened family of receptors. Thus, the only structural feature that all G-protein-coupled receptors have in common is the seven-transmembrane helical bundle. Nevertheless, most non-rhodopsin-like receptors do have certain minor structural features in common with the rhodopsin-like receptors — for example, a disulfide bridge between the top of TM-III and the middle of extracellular loop-3, and a cluster of basic residues located just below TM-VI. 

FIGURE 2.3 The three main families of mammalian G-protein-coupled 7TM receptors in mammals. No obvious sequence identity is found between the rhodopsin-like family A, the glucagon/VIP/calcitonin family B, and the metabotropic glutamate/chemosensor family C of G-protein-coupled 7TM receptors, with the exception of the disulfide bridge between the top of TM-III and the middle of extracellular loop-2 (see Figure 2.2). Similarly, no apparent sequence identity exists among members of these three families and, for example the 7TM bitter taste receptors, the V1R pheromone receptors, and the 7TM frizzled proteins, which all are either known or believed to be G-protein-coupled receptors. Bacteriorhodopsins, which are not G-protein-coupled proteins but proton pumps, are totally different in respect to amino-acid sequence but have a seven-helical bundle arranged rather similarly to that for the G-protein-coupled receptors. 

In the x-ray structure of rhodopsin, an amphipathic helix runs parallel to the membrane from the intracellular end of TM-VII beneath the seven-helical bundle to the other side of TM-I and TM-II. At this point, one or more Cys residues are often found and are known to be subject to a dynamic posttranslational modification with palmitic acid residues. Like the phosphorylation event, the palmitoylation process appears to be dynamically regulated by receptor occupancy and is also involved in the desensitization phenomenon. The two posttranslational modifications can influence each other. For example, the conformational constraint induced by palmitoylation may alter the accessibility of certain phosphorylation sites. Like the phosphorylation process, the functional consequences of palmitoylation also appear to vary from receptor to receptor. 

The N-terminal domain of the OCP is an orthogonal alpha-helical bundle, subdivided into two four-helix bundles (Figure 1.3a and c). These subdomains are composed of discontinuous segments of the polypeptide chain (gray and white in Figure 1.3c). To date, the OCP N-terminal domain is the only known protein structure with this particular fold (Pfam 09150). The hydroxyl terminus of the 3 -hydroxyechinenone is nestled between the two bundles. The C-terminal domain (dark... 

Here, the components of hCT molecules observed by the DDMAS and CPMAS experiments are defined as A and B forms, respectively. For early stages, it is proposed163 that a formation of micelles corresponding to the a-helical bundle is reversibly formed from the monomers with the same aggregation number n0 (An0),... 

Figure 22 Schematic representation of proposed models for the fibril formation in the cases of pH 3.3 and 7.5. (A) hCT monomers in solution (B) a homogeneous association to form the a-helical bundle (micelle) (C) a homogeneous nucleation process to form the P-sheet and heterogeneous association process (D) a heterogeneous fibrillation process to grow a large fibril, a-helix, antiparallel p-sheet, and parallel p-sheet forms are shown by a box, drawn by dark grey and grey, respectively. From Ref. 163 with permission.

Elling, C. E. and Schwartz, T. W. (1996) Connectivity and orientation of the seven helical bundle in the tachykinin NK-1 receptor probed by zinc site engineering. limbo. J. 15,6213-6219. 

Figure 4.11 (a) Four helix bundle domain proteins, illustrated by myohaemerythrin. The oxygenbinding site is located at the di-iron centre within the hydrophobic core of the helical bundle, (b) The globin fold, represented here by myoglobin. (From Branden and Tooze, 1991. Reproduced by permission of Garland Publishing, Inc.)... 

There is a correlation between the backbone conformations which commonly flank disulfides and the frequency with which disulfides occur in the different types of overall protein structure (see Section III,A for explanation of structure types), although it is unclear which preference is the cause and which the effect. There are very few disulfides in the antiparallel helical bundle proteins and none in proteins based on pure parallel /3 sheet (except for active-site disulfides such as in glutathione reductase). Antiparallel /3 sheet, mixed /8 sheet, and the miscellaneous a proteins have a half-cystine content of 0-5%. Small proteins with low secondary-structure content often have up to 15-20% half-cystine. Figure 52 shows the structure of insulin, one of the small proteins in which disulfides appear to play a major role in the organization and stability of the overall structure. 

The first designed catalyst where there was some understanding of the relationship between structure and function was oxaldie 1, a 14-residue peptide that folds in solution to form helical bundles [11] (Fig. 12). Oxaldie 1 was designed to catalyze the decarboxylation of oxaloacetate, the a-keto acid of aspartic acid, via a mechanism where a primary amine reacts with the ketone carbonyl group to form a carbinolamine that is decarboxylated to form pyruvate. The reaction is piCj dependent and proceeds faster the lower the piC of the primary amine if the reaction is carried out at a pH that is lower than the piCj, of the reactive amine. The sequence contains five lysine residues that in the folded state form... 

Tamaru S, Takeuchi M, Sano M, Shinkai S (2002) Sol-gel transcription of sugar-appended porphyrin assemblies into fibrous silica unimolecular stacks versus helical bundles as templates. Angew Chem Int Ed 41 853-856... 

B. Bilgiger, K. Kumar, De novo design of defined helical bundles in membrane environments, Proc. Natl. Acad. Sci. USA 101 (2004) 15324-15329. 

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