Conformational analysis of peptides corresponding to all the secondary structure elements of protein L B1 domain: Secondary structure propensities are not conserved in proteins with the same fold

Ramı́rez-Alvarado, Marina; Serrano, Luís; Blanco, Francisco J.

doi:10.1002/pro.5560060119

Cited by 47 publications

(41 citation statements)

References 72 publications

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“…The homologous decapeptide, A␤ (21)(22)(23)(24)(25)(26)(27)(28)(29)(30), displayed protease resistance identical to that of full-length A␤, suggesting that this region could organize monomer folding and thus be a folding nucleus. This suggestion was consistent with the observation that many folding nuclei studied in isolation are structurally stable (12)(13)(14)(15)(16). In fact, NMR studies of the A␤ (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) peptide revealed a turn in the Val-24-Lys-28 region that was stabilized by hydrophobic interactions between the isopropyl and n-butyl side chains of Val-24 and Lys-28, respectively, and by long-range electrostatic interactions between the N ⑀ cation of Lys-28 and the side-chain carboxylate anions of Glu-22 or Asp-23 (11).…”

supporting

confidence: 92%

“…In studies of ␥-secretase, the enzyme complex that releases A␤ from A␤PP through cleavage at the A␤ C terminus (45), Zhang et al (46) have shown that the region of A␤PP immediately preceding the transmembrane domain [equivalent to A␤ (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)] affects the intramembranous proteolytic processing that produces A␤40, A␤42, and related A␤ isoforms. In particular, Ser-26 and Lys-28 have been found to be key residues controlling this process (47).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Familial Alzheimer's disease mutations alter the stability of the amyloid β-protein monomer folding nucleus

Grant

Lazo

Lomakin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

119

194

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Amyloid ␤-protein (A␤) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). Recently, to elucidate the oligomerization pathway, we studied A␤ monomer folding and identified a decapeptide segment of A␤, 21 Ala-22 Glu-23 Asp-24 Val-25 Gly-26 Ser-27 Asn-28 Lys-29 Gly-30 Ala, within which turn formation appears to nucleate monomer folding. The turn is stabilized by hydrophobic interactions between Val-24 and Lys-28 and by longrange electrostatic interactions between Lys-28 and either Glu-22 or Asp-23. We hypothesized that turn destabilization might explain the effects of amino acid substitutions at Glu-22 and Asp-23 that cause familial forms of AD and cerebral amyloid angiopathy. To test this hypothesis, limited proteolysis, mass spectrometry, and solution-state NMR spectroscopy were used here to determine and compare the structure and stability of the A␤(21-30) turn within wild-type A␤ and seven clinically relevant homologues. In addition, we determined the relative differences in folding free energies (⌬⌬G f) among the mutant peptides. We observed that all of the disease-associated amino acid substitutions at Glu-22 or Asp-23 destabilized the turn and that the magnitude of the destabilization correlated with oligomerization propensity. The Ala21Gly (Flemish) substitution, outside the turn proper (Glu-22-Lys-28), displayed a stability similar to that of the wild-type peptide. The implications of these findings for understanding A␤ monomer folding and disease causation are discussed.A bundant evidence links the amyloid ␤-protein (A␤) with the neuropathogenesis of Alzheimer's disease (AD) (for recent reviews, see refs. 1 and 2). A␤ is a normal metabolite of the A␤ precursor (A␤PP), from which A␤ is produced by endoproteolysis (3). Two predominant forms of A␤ exist in vivo, A␤40 and A␤42, which are 40-and 42-aa in length, respectively (2, 4, 5). Recent experimental and clinical evidence suggests that the primary neurotoxins in AD are A␤ oligomers or protofibrils (1, 6-10). Understanding the folding and oligomerization of nascent A␤ monomers thus has become an especially important aspect of current strategies for understanding AD etiology and developing therapeutic agents.We have applied a multidisciplinary approach to the A␤ assembly problem. Initial studies used limited proteolysis coupled with mass spectrometry to determine whether monomeric A␤ possessed any stable or quasistable structure that could protect the peptide from proteolysis. Surprisingly, a 10-residue segment within both A␤40 and A␤42, Ala-21-Ala-30, was identified (11). The homologous decapeptide, A␤(21-30), displayed protease resistance identical to that of full-length A␤, suggesting that this region could organize monomer folding and thus be a folding nucleus. This suggestion was consistent with the observation that many folding nuclei studied in isolation are structurally stable (12-16). In fact, NMR studies of the A␤(21-30) peptide revealed a turn in the Val-24-Lys-28 region that was stabilized by hydrophobic interactions between...

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supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Familial Alzheimer's disease mutations alter the stability of the amyloid β-protein monomer folding nucleus

Grant

Lazo

Lomakin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

119

194

View full text Add to dashboard Cite

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“…Notwithstanding the disrupting effects of TFE on the tertiary structure of oligomeric complexes, peptide-peptide interactions producing stable oligomers have been documented at concentrations of TFE as high as 50% (70). Interestingly, the TFE concentration used in our experiments (30%) has been reported to yield for numerous peptides secondary structures that compare favorably with those of the native systems (71)(72)(73).…”

Section: Trimeric Coiled-coil Modelmentioning

confidence: 70%

Assembly of a Ternary Complex by the Predicted Minimal Coiled-coil-forming Domains of Syntaxin, SNAP-25, and Synaptobrevin

Cánaves

Montal

1998

Journal of Biological Chemistry

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The assembly of target (t-SNARE) and vesicle-associated SNAP receptor (v-SNARE) proteins is a critical step for the docking of synaptic vesicles to the plasma membrane. Syntaxin-1A, SNAP-25, and synaptobrevin-2 (also known as vesicle-associated membrane protein, or VAMP-2) bind to each other with high affinity, and their binding regions are predicted to form a trimeric coiledcoil. Here, we have designed three peptides, which correspond to sequences located in the syntaxin-1A H3 domain, the C-terminal domain of SNAP-25, and a conserved central domain of synaptobrevin-2, that exhibit a high propensity to form a minimal trimeric coiled-coil. The peptides were synthesized by solid phase methods, and their interactions were studied by CD spectroscopy. In aqueous solution, the peptides were unstructured and showed no interactions with each other. In contrast, upon the addition of moderate amounts of trifluoroethanol (30%), the peptides adopted an ␣-helical structure and displayed both homomeric and heteromeric interactions. The interactions observed in ternary mixtures induce a stabilization of peptide structure that is greater than that predicted from individual binary interactions, suggesting the formation of a higher order structure compatible with the assembly of a trimeric coiled-coil.The assembly of the synaptic core complex is essential for Ca 2ϩ -dependent neuroexocytosis. This early event in the secretory cascade is then followed by the priming and vesicle fusion steps (1-6). According to the SNARE 1 model, docking of synaptic vesicles to the plasma membrane is a critical step that involves the formation of a ternary complex by the v-SNARE synaptobrevin (also known as vesicle-associated membrane protein, or VAMP), and two t-SNAREs: SNAP-25 and syntaxin (7-9). Reconstitution of the v-SNARE synaptobrevin into lipid vesicles and the two t-SNAREs, SNAP-25 and syntaxin, into a distinct vesicle pool has provided evidence that the formation of a ternary complex is sufficient to join the independent vesicle pools and lead to fusion of the apposed bilayer membranes (10).Understanding the interactions between the proteins of the trimeric complex in a simplified model may outline new ways to control its assembly and dissociation or to modulate the conformational changes that are presumably necessary for the progression from the docking step to the subsequent phases in the secretory process. The structural domains that appear to be implicated in the protein-protein interactions between SNAP-25, synaptobrevin, and syntaxin show a high propensity for the formation of ␣-helices (11-15). Secondary structure analysis shows that the periodic distribution of hydrophobic amino acids is consistent with a coiled-coil organization (2, 11, 12, 14, 15). Fluorescence energy transfer experiments (12) and electron microscopy (15) further indicate that synaptobrevin and syntaxin are aligned in parallel in the context of a ternary coiled-coil.To investigate the postulated coiled-coil interactions between the proteins that constitute the d...

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“…The structures of peptides corresponding to portions of complete native sequences have been investigated to identify parts of the sequence that adopt the native conformation early, as well as parts that undergo transitions (23,24). Whereas some peptide fragments adopt stable conformations similar to those seen in the complete protein (25,26), other peptides adopt different secondary structure in different contexts (27)(28)(29)(30)(31)(32)(33). As shown by Minor and Kim (34), the same local 11-aa sequence can adopt ␤-strand or ␣-helix structure, if inserted at two different positions in protein G. Also, for prion proteins, it appears that the same sequence can adopt different tertiary folds with different secondary structure (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48).…”

mentioning

confidence: 99%

Coupled prediction of protein secondary and tertiary structure

Meiler

Baker

2003

Proc. Natl. Acad. Sci. U.S.A.

174

130

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The strong coupling between secondary and tertiary structure formation in protein folding is neglected in most structure prediction methods. In this work we investigate the extent to which nonlocal interactions in predicted tertiary structures can be used to improve secondary structure prediction. The architecture of a neural network for secondary structure prediction that utilizes multiple sequence alignments was extended to accept low-resolution nonlocal tertiary structure information as an additional input. By using this modified network, together with tertiary structure information from native structures, the Q3-prediction accuracy is increased by 7-10% on average and by up to 35% in individual cases for independent test data. By using tertiary structure information from models generated with the ROSETTA de novo tertiary structure prediction method, the Q3-prediction accuracy is improved by 4 -5% on average for small and medium-sized single-domain proteins. Analysis of proteins with particularly large improvements in secondary structure prediction using tertiary structure information provides insight into the feedback from tertiary to secondary structure.artificial neural networks ͉ protein folding ͉ ROSETTA ͉ fragment replacement ͉ CASP M any approaches for predicting secondary structure from sequence have been developed (1-13). The PHD program published by Rost and Sander (14,15) used multiple sequencesequence alignments for the first time. The state-of-the-art PSIPRED program by Jones (16) uses position-specific scoring matrices obtained in PSIBLAST searches (17). The most accurate of these methods achieve a Q 3 score between 75% and 80%, where Q 3 is the percentage of amino acids correctly predicted as helix, sheet, or coil if all amino acids are classified in one of the three groups. Not only secondary structure but also supersecondary structural elements such as U-turns or ␤-hairpins can be predicted from sequence (18)(19)(20)(21)(22). In essentially all previous work, the prediction of the secondary structure at a given position i is based entirely on a local sequence window of 5-27 aa centered on the position; sequence information distant from position i is ignored, although, during folding, interactions with residues distant along the linear sequence but close in space are likely to influence the structure at position i.During the folding process of a protein, a certain fragment first might adopt a secondary structure preferred by the local sequence (e.g., an ␣-helix) and later be transformed to another secondary structure (e.g., a ␤-strand) because of nonlocal interactions with a segment distant along the sequence (Fig. 1). The structures of peptides corresponding to portions of complete native sequences have been investigated to identify parts of the sequence that adopt the native conformation early, as well as parts that undergo transitions (23,24). Whereas some peptide fragments adopt stable conformations similar to those seen in the complete protein (25, 26), other peptides adopt different seco...

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Conformational analysis of peptides corresponding to all the secondary structure elements of protein L B1 domain: Secondary structure propensities are not conserved in proteins with the same fold

Cited by 47 publications

References 72 publications

Familial Alzheimer's disease mutations alter the stability of the amyloid β-protein monomer folding nucleus

Familial Alzheimer's disease mutations alter the stability of the amyloid β-protein monomer folding nucleus

Assembly of a Ternary Complex by the Predicted Minimal Coiled-coil-forming Domains of Syntaxin, SNAP-25, and Synaptobrevin

Coupled prediction of protein secondary and tertiary structure

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