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-stacking in the self-assembly of amyloid fibrils
Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel Aviv 69978, Israel
1Correspondence: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel. E-mail: ehudg{at}post.tau.ac.il
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ABSTRACT |
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 TOP ABSTRACT THE ROLE OF {pi}-STACKING...AMYLOID FORMATIONAROMATIC RESIDUES IN SHORT...THE ROLE OF {pi}-STACKING...IMPLICATIONS OF THE {pi}...CONCLUSIONSREFERENCES |
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- interactions may play a significant role in the molecular recognition and self-assembly processes that lead to amyloid formation. This is in line with the well-known central role of -stacking interactions in self-assembly processes in the fields of chemistry and biochemistry. We speculate that the stacking interactions may provide energetic contribution as well as order and directionality in the self-assembly of amyloid structures. Experimental data regarding amyloid formation and inhibition by short peptide analogs also support our hypothesis. The -stacking hypothesis suggests a new approach to understanding the self-assembly mechanism that governs amyloid formation and indicates possible ways to control this process.—Gazit, E. A possible role for -stacking in the self-assembly of amyloid fibrils.
Key Words: Alzheimer’s disease • aromatic residue • amyloid-related proteins
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THE ROLE OF -STACKING IN SELF-ASSEMBLY PROCESSES
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TOPABSTRACTTHE ROLE OF {pi}-STACKING...AMYLOID FORMATIONAROMATIC RESIDUES IN SHORT...THE ROLE OF {pi}-STACKING...IMPLICATIONS OF THE {pi}...CONCLUSIONSREFERENCES |
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2
3
4)
. Extensive theoretical and empirical studies have shown that aromatic rings tend to form high-order clusters of four different types: parallel displaced, T-shaped, parallel staggered, or Herringbone (5
; Fig. 1
A). All four geometries are possible potential minimum configurations in the Lennard-Jones-Coulomb empirical potential calculations (5)
. The attractive nonbonded interactions between planar aromatic rings are referred to as - interactions or -stacking. The steric constrains associated with the formation of these ordered stacking structures have a fundamental role in self-assembly processes leading to the formation of supramolecular structures (1
2
3
4
5
6)
. Such -stacking interactions stabilize the double-helix structure of DNA involved in core packing and stabilization of the tertiary structure of proteins, host–guest interactions, and porphyrin aggregation in solution (1
2
3
4)
. It was suggested that -stacking energy may be largely driven-by entropy (6)
. Accordingly, ordered water molecules are being released from the aromatic rings upon intermolecular interaction. Therefore, despite the ordered structures formed by the stacking interactions, the overall entropy of the thermodynamic system, which includes bound water molecules, increases.
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AMYLOID FORMATION |
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TOPABSTRACTTHE ROLE OF {pi}-STACKING...AMYLOID FORMATIONAROMATIC RESIDUES IN SHORT...THE ROLE OF {pi}-STACKING...IMPLICATIONS OF THE {pi}...CONCLUSIONSREFERENCES |
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8
9
10
). Amyloid formation is a process in which normal well-folded cellular proteins undergo a self-assembly process that leads to the formation of large and ordered protein structures.
This self-assembly process is accompanied by a structural transition of the aggregated proteins from their normal fold into a predominantly ß-sheet secondary structure. Though there is no sequence homology between the different amyloid-related proteins, the amyloid structures formed share similar ultrastructural properties as determined by electron microscopy and X-ray fiber diffraction, and thus may reflect a generic structure for aggregated proteins (7
8
9
10
11
12)
. Another characteristic of amyloid fibrils observed more than 40 years ago is a distinct green birefringence after staining of the amyloid with the aromatic Congo red dye (7
8
9
10
11
12)
. This is in marked contrast to nonspecific protein aggregation for which no ordered microscopic structure, diffraction pattern, or birefringence is observed. All of the above suggests that a specific pattern of molecular interactions, rather than nonspecific hydrophobic interactions, should play a role in the formation of such an ordered amyloidal structure. However, despite the great clinical importance of the amyloid formation process, no such generic pattern of molecular interactions has been identified.
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AROMATIC RESIDUES IN SHORT AMYLOID-RELATED PEPTIDE |
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TOPABSTRACTTHE ROLE OF {pi}-STACKING...AMYLOID FORMATIONAROMATIC RESIDUES IN SHORT...THE ROLE OF {pi}-STACKING...IMPLICATIONS OF THE {pi}...CONCLUSIONSREFERENCES |
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). Such a frequent occurrence of aromatic residues raises the possibility that these residues may play a significant role in the amyloid formation process by serving as structural and functional elements that direct molecular recognition and self-assembly. This is in line with the well-known central role of -stacking interactions in chemistry and biochemistry (1
2
3
4
5
6)
.
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The relative frequency of occurrence of aromatic residues in proteins in general is low. The three aromatic amino acids are among the group of six amino acids with the lowest frequency of occurrence in proteins (histidine, which may also be considered aromatic, methionine, and cysteine are the other three). Tryptophan is the amino acid with the lowest frequency of occurrence (1.32%); the occurrence of tyrosine and phenylalanine is 3.25% and 3.91%, respectively. The amino acid occurrence statistics were compiled using the NCBI database (13)
.
At the same time, aromatic residues are highly conserved (14)
. When families of proteins are being analyzed statistically, tryptophan is by far the most conserved residue. Phenylalanine and tyrosine are also highly conserved, sharing third place only with methionine (cysteine is the second most conserved amino acid). When amino acids changes do occur, it is rare that a nonaromatic residue will be replaced with an aromatic one and vice versa, suggesting a significant role for aromatic residues in structural biology.
Islet amyloid polypeptide
The first and most striking example for a possible role of aromatic residues in amyloid formation is the recently determined minimal amyloid-forming fragment (15)
of the 37 amino acid islet amyloid polypeptide (IAPP), or amylin (12
, 15
16
17
18
19)
. IAPP deposits are found postmortem in more than 95% of patients with type II diabetes, and the peptide has been shown to form amyloid fibers in vitro (16
17)
. A six residue peptide fragment of human IAPP (NFGAIL) has been shown to form amyloid fibrils similar to those formed by the full-length protein (15)
; thus, it seems to serve as the ‘basic amyloidogenic unit’ for this polypeptide. A shorter, five residue fragment (FGAIL) also forms ordered amyloid fibrils. However, these fibrils are different in morphology from the full-length peptide (15)
. A shorter peptide corresponding to the GAIL sequence did not form any fibrils at all (15)
. Analysis of the physicochemical properties of these three short peptides suggests that the phenylalanine residue present in the peptides is a residue that must have a major role as a structural element in the self-assembly process of these short peptides. This is because the other residues in pentapeptide (glycine, alanine, isoleucine, leucine) do not have the physicochemical properties needed to direct a process of specific molecular recognition and self-assembly. Furthermore, a clue as to the role of aromatic interactions in the early steps of fibril formation by IAPP stems from analysis of the near-UV CD spectrum of IAPP, which shows stacking of aromatic rings just before the appearance of insoluble fibrils (19)
. When we recently preformed an alanine scan of the ‘basic amyloidogenic unit’ of IAPP, the significant role of the phenylalanine residue was clearly demonstrated (12)
.
Recent studies have demonstrated that other two fragments of IAPP that contain aromatic residues (TNVGSNTY and QRLANFLVH) can form fibrillar structures in vitro (refs 20
, 21
, respectively). However, in both cases the fragments are significantly longer than the FGAIL peptide and the amino acid composition is significantly more complex. Additional research is needed in order to determine the minimal active sequence and the possible role of aromatic residue in the process of amyloid formation.
Alzheimer’s ß-amyloid
Another example of an amyloid-related very short peptide that contains aromatic residues is the minimal fragment that mediates binding of Alzheimer’s ß-amyloid (Aß) polypeptides (22)
. Brain senile amyloid plaques composed of the Aß peptide are directly correlated with the pathogenesis of Alzheimer’s disease. A short fragment of Aß that contains two phenylalanine residues (QKLVFF) was shown to bind specifically to full-length peptide (22)
. The short peptide could inhibit amyloid formation by the full-length Aß polypeptide (22)
. Follow-up studies have shown that not only QKLVFF, but also LVFFA and its derivatives (23)
and LPFFD (24)
, are all potent inhibitors of amyloid formation by Aß polypeptide. Another recent study demonstrated that a seven amino acid fragment of Aß, KLVFFAE, forms well-ordered amyloid fibrils (25)
. These findings point to the pair of phenylalanine residues as the major structural element that mediates binding of the QKLVFF peptide to the Aß polypeptide. As the formation of amyloid fibrils is first of all a process of molecular recognition and self-assembly, the high affinity and selectivity of the FF motif seems to provide the molecular recognition element needed for such process in the context of the full-length Aß.
Aortic medial amyloid
One more example of a short functional peptide that contains aromatic residues is the octapeptide fragment (NFGSVQFV) of the 364 amino acid lactadherin protein, the precursor protein for the 5.5 kDa peptide component of the aortic medial amyloid (26)
. Aortic medial amyloid is a form of localized amyloid that occurs in virtually all individuals older than 60 years (27)
. Amino acid sequence analysis of the 5.5 kDa peptide that composes the aortic medial amyloid demonstrated that the amyloid deposit is derived from an integral proteolytic fragment of lactadherin (26)
. When the NFGSVQFV octapeptide fragment derived from the 5.5 kDa peptide was synthesized and characterized, it was shown to form amyloid deposits as the 5.5 kDa parent peptide (26)
. A part of the molecule (i.e., NFGXXX) resembles the short fragment of IAPP. The length of the peptide studied was chosen arbitrarily; the minimal fragment of lactadherin needed to form amyloid fibrils with similar properties as the parent molecule is still unknown, and may be shorter. We are studying the effects of substitutions of the aromatic residues on amyloid formation in the case of aortic medial amyloid. Preliminary data clearly indicate that some, but not all, aromatic residues play a role in amyloid formation (E. Gazit et al., unpublished results).
Finnish hereditary and chronic inflammation amyloidosis
Other amyloid-related sequences in which short functional aromatic-containing peptides were found are the SFNNGDCCFILD (28)
and SFFSFLGEAFD (29)
peptides from gelsolin and serum amyloid A, respectively. Fragments of gelsolin and serum amyloid A proteins were found in cases of Finnish hereditary amyloidosis (28)
and chronic inflammation amyloidosis (29)
, respectively. In both cases, the peptides were identified as short peptide fragments of the parent proteins that can form amyloid fibrils by themselves. Although both peptides contain a considerable number of aromatic residues (phenylalanine in all cases), they are too complex to state that the phenylalanine should be described as the sole structural element needed to dictate molecular specificity.
Animal and yeast prions
The last examples of occurrence of aromatic residues in amyloid formation process are the peptide repeats of animal and yeast prion proteins. Animal prion diseases are sporadic or inherited neurodegenerative disorders that are transmitted by a protein infective agent. The agent is a misfolded form (PrS) of a normal cell protein (PrP) that acts by a conversion of normal folded PrP proteins to amyloid-like aggregates (30)
. The importance of the octapeptide repeats in the pathogenesis of prion diseases is clearly revealed by the fact that most of the inherited forms of prion disease (e.g., Creutzfeldt-Jacob disease, Gerstmann-Sträussler-Scheinker disease, atypical dementia, and others) result from the insertion of one to nine extra octapeptide repeats in addition to the five repeats that occur in the normal prion protein (see review by Priola and Chesebro, ref 31
).
Later studies demonstrated that the prion phenomenon is not restricted to mammalian proteins, but several yeast proteins have molecular properties that resemble animal prion proteins. One example is a misfolded variant (Sup35p) of a normal cellular protein (Sup35), which has been shown to cause a change in the phenotype of a normal cell by converting the normal protein into aggregates (32)
. As in the animal prion proteins, oligopeptide repeats were also found in the Sup35 yeast protein (33)
.
The specific role of these repeats in the mechanism of the yeast prion transformation was recently shown by fusion of the repeats to a heterologous protein (34)
. In this experiment, only the amino-terminal part of the Sup35 protein, which includes the peptide repeats, was fused to the structurally and functionally unrelated hormone-regulated transcription factor, the rat glucocorticoid receptor (GR). As with the wild-type Sup35 protein, the engineered GR protein underwent functional inactivation apparently due to protein aggregation. The apparent role of protein aggregation was demonstrated by the ability of guanidine hydrochloride and the protein remodeling factor Hsp 104 to transform the engineered protein back into an active state, as observed with Sup 35. Moreover, the pattern of inheritance of the engineered protein was shown to have the traits as of a naturally occurring Sup35 protein (35)
, thus proving the central role of the repeats in the mediation of this mechanism. A recent study demonstrated that a short aromatic heptamer peptide (GNNQQNY) derived from the Sup35 protein, which resembles the oligopeptide repeat, could form amyloid fibrils in vitro.
Other amyloid-related proteins
Aromatic residues are also present in other polypeptides that play a role in amyloid-related diseases (Table 2
). One example is a phenylalanine near the carboxyl terminus of NAC (non-Aß component of Alzheimer’s disease), a 35 residue peptide fragment of 
-synuclein or NACP protein that was originally isolated from the insoluble core of AD amyloid plaques (36)
. The occurrence of this phenylalanine residue by itself is not unusual, but in combination with the data presented above may provide direction for further exploration of NAC aggregation.
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Another example is the occurrence of several conserved phenylalanine residues in calcitonin, a short peptide known to form amyloid fibrils both in vivo and in vitro (37
, 38)
that is associated with medullary thyroid carcinoma (39)
. A third example is the human BRI gene located on chromosome 13; its amyloid fibrils are associated with neuronal dysfunction and dementia (40)
. In this case, several phenylalanine residues are observed. However, their pattern does not resemble that of the calcitonin. As with NAC, the occurrence of these phenylalanine residues in itself is not unusual, but provides a clue to further experimental exploration.
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THE ROLE OF -STACKING INTERACTIONS IN CHEMISTRY
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TOPABSTRACTTHE ROLE OF {pi}-STACKING...AMYLOID FORMATIONAROMATIC RESIDUES IN SHORT...THE ROLE OF {pi}-STACKING...IMPLICATIONS OF THE {pi}...CONCLUSIONSREFERENCES |
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-stacking interactions in the formation of amyloid deposits stems from the fact that (as described earlier) attractive nonbonded interactions between aromatic rings are very common in many areas of chemistry. Moreover, these interactions have a key role in processes of molecular recognition and self-assembly (1
2
3
4
5
6)
. As amyloid fibril formation is basically a process of intermolecular recognition and self-assembly, the -stacking can provide two key elements that are highly important for the formation of such structures: 1) an energetic contribution that stems from the stacking itself; such a contribution can thermodynamically drive the self-assembly process, and 2) specific directionality and orientation provided by the specific pattern of stacking. This is especially important since amyloid fibrils are well-defined supramolecular structures and a specific pattern of stacking should lead to a formation of an ordered structure. This is in contrast to nonamyloidal protein aggregation, which leads to the formation of amorphous aggregates. As mentioned above, there are four possible ways for -stacking (4)
. Analysis of -stacking in a group of proteins with known structures suggests a parallel displaced -stacking to be the major organization of - interactions in proteins (5
; Fig. 1A
). In these interactions, the aromatic rings are in an off-centered parallel orientation (5
; Fig. 1A
). We assume a cluster organization may be present in the amyloidal structure as well. Each of the four possible precise planar orientations may account for the regulatory nature of amyloid structures and the formation of a structure with a well-ordered 3-dimensional pattern.
The mechanism of amyloid formation suggested (Fig. 1B
) includes a stepwise assembly of short recognition elements. At the first stage, two structural elements that contain aromatic residues form a bimolecular structure, which is restricted by the allowed geometry of - stacking. This is followed by a stepwise addition of further monomers containing the same recognition elements. Again, the overall structural organization of the addition process is being directed by the restricted geometries of the stacking interaction.
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IMPLICATIONS OF THE -STACKING HYPOTHESIS FOR THE CONTROL OF AMYLOID FORMATION
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TOPABSTRACTTHE ROLE OF {pi}-STACKING...AMYLOID FORMATIONAROMATIC RESIDUES IN SHORT...THE ROLE OF {pi}-STACKING...IMPLICATIONS OF THE {pi}...CONCLUSIONSREFERENCES |
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8
9
10
11
12
, 41)
. The current crisis stems from 1) the sharp increase in the occurrence of genetic and sporadic amyloid diseases, many of which are correlated with the growing life expectancy of the Western population; and 2) the outbreak of a major infectious protein misfolding disease, bovine spongiform encephalopathy (BSE). It is therefore important to explore new ways to understand and control the processes of amyloid formation.
Physical blockage of the self-assembly process is one way to clinically control amyloidal diseases. Our hypothesis regarding the role of -stacking in amyloid formation suggests that drugs that can block -stacking interactions may be potent candidates for the control of amyloid diseases. Recent studies (22
, 42)
in fact have shown the effectiveness of small molecules that contain aromatic residues in controlling the formation of the Aß polypeptide, Ro 65–8815/001 (42)
, and 3-p-toluoyl-2-(4'-(3-diethylaminopropoxy)-phenyl]-benzofuran (43
; Fig. 2
A, b and c, respectively). Earlier studies demonstrated the ability of various short peptide analogs that contain the FF motif to inhibit amyloid formation by the Aß peptide (22
23
24)
. It was also observed that Congo red (Fig. 2A, c
), the specific amyloid binding dye, inhibits amyloid fibril formation by Aß (44)
. The physicochemical profile of Congo red (Fig. 2A, a
) suggests that aromatic elements are the major structural and functional elements in this compound. This may suggest that the stacking of aromatic moieties may facilitate the interaction of Congo red with amyloid fibrils. Congo red interacts with Aß at the same binding site as Ro 65–8815/001 (42)
. Moreover, it was shown that both the anticancer drug 4'-iodo-4'-deoxydoxorubicin (Figs. 2
A, d) and the antibiotic tetracycline (Figs. 2
A, e) inhibit amyloid formation (45
46
47
48)
. Although the structural features of the two molecules are more complex than that of Congo red, both drugs share the basic polyaromatic nature. An intriguing point is the observation that 4'-iodo-4'-deoxydoxorubicin, like Congo red, is a generic anti-amyloid agent that inhibits amyloid formation by five unrelated proteins (45)
.
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Although the use of known aromatic drugs is important in controlling amyloid formation, it has several drawbacks in terms of specificity (the minimal concentration needed to inhibit the formation of fibrils) and side effects. A more direct approach to control specific forms of amyloid formation is to take advantage of the high affinity and specificity of the short aromatic ‘molecular recognition elements’ mentioned in this study. The approach is based on the use of aromatic recognition elements exactly as they appear in the amyloid-forming proteins or peptides, conjugated to breakers of the amyloid self-assembly process (Fig. 2B
). One direction for such breakage, as demonstrated in Fig. 2B, is
to attach charged amino acids to the recognition element. In this way, mixed peptide inhibitor complexes will electrostatically block the progress of the self-assembly process. Other possibilities for such blockage are to place bulky moieties that will sterically block molecular interactions or ß-breaker amino acids such as proline, glutamic acid, or aspartic acid, which will affect the structure of the stacked assembly. The latter two amino acids allow introduction of the charge as well as ß-strand breakage. This approach was successfully used to arrest of amyloid fibril formation by the Aß peptide (24)
. We are using this approach to develop lead molecules that specifically block amyloid formation by IAPP (E. Gazit et al., unpublished results).
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CONCLUSIONS |
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TOPABSTRACTTHE ROLE OF {pi}-STACKING...AMYLOID FORMATIONAROMATIC RESIDUES IN SHORT...THE ROLE OF {pi}-STACKING...IMPLICATIONS OF THE {pi}...CONCLUSIONSREFERENCES |
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- interactions in chemistry, we speculate a role for the aromatic residues in self-assembly processes that lead to amyloid formation. Further experimental work should be undertaken investigate this hypothesis. Experiments along the line of this hypothesis should be useful in identifying novel structural elements that play a role in amyloid formation and further facilitate the development of specific inhibitors of the process.
Received for publication June 15, 2001.
Revision received October 8, 2001.
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TOPABSTRACTTHE ROLE OF {pi}-STACKING...AMYLOID FORMATIONAROMATIC RESIDUES IN SHORT...THE ROLE OF {pi}-STACKING...IMPLICATIONS OF THE {pi}...CONCLUSIONSREFERENCES |
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