Sequence and Structure Analysis of Parallel β Helices: Implication for Constructing Amyloid Structural Models

Tsai, Hui‐Hsu Gavin; Gunasekaran, Kannan; Nussinov, Ruth

doi:10.1016/j.str.2006.03.015

Cited by 40 publications

(46 citation statements)

References 64 publications

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“…In contrast to heterologous sequences the ability of homologous sequences to stack in a parallel fashion has a higher probability because identical residues in the parallel strand will stack perfectly (unless they are charged). A Val-Val stack or an Asnladder are well known examples (31). However, in the case of rung 6 and 7, a heterologous combination of two different peptides is required.…”

Section: Resultsmentioning

confidence: 99%

Heterologous Stacking of Prion Protein Peptides Reveals Structural Details of Fibrils and Facilitates Complete Inhibition of Fibril Growth

Boshuizen

Schulz

Morbin

et al. 2009

Journal of Biological Chemistry

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Fibrils play an important role in the pathogenesis of amyloidosis; however, the underlying mechanisms of the growth process and the structural details of fibrils are poorly understood. Crucial in the fibril formation of prion proteins is the stacking of PrP monomers. We previously proposed that the structure of the prion protein fibril may be similar as a parallel left-handed ␤-helix. The ␤-helix is composed of spiraling rungs of parallel ␤-strands, and in the PrP model residues 105-143 of each PrP monomer can contribute two ␤-helical rungs to the growing fibril. Here we report data to support this model. We show that two cyclized human PrP peptides corresponding to residues 105-124 and 125-143, based on two single rungs of the lefthanded ␤-helical core of the human PrP Sc fibril, show spontaneous cooperative fibril growth in vitro by heterologous stacking. Because the structural model must have predictive value, peptides were designed based on the structure rules of the lefthanded ␤-helical fold that could stack with prion protein peptides to stimulate or to block fibril growth. The stimulator peptide was designed as an optimal left-handed ␤-helical fold that can serve as a template for fibril growth initiation. The inhibiting peptide was designed to bind to the exposed rung but frustrate the propagation of the fibril growth. The single inhibitory peptide hardly shows inhibition, but the combination of the inhibitory with the stimulatory peptide showed complete inhibition of the fibril growth of peptide huPrP-(106 -126). Moreover, the unique strategy based on stimulatory and inhibitory peptides seems a powerful new approach to study amyloidogenic fibril structures in general and could prove useful for the development of therapeutics.Transmissible spongiform encephalopathies are neurodegenerative disorders in a wide range of mammalian species, including Creutzfeldt-Jacob disease in man, scrapie in sheep, and bovine spongiform encephalopathy in cattle. The deposition of aggregated prion protein fibrils on and in neurons is regarded to be the source of these neurodegenerative diseases and is frequently associated with occurrence of Congo red positivity (1-3). It is still unknown how much of the whole PrP Sc molecule is involved in the fibril growth. It is shown that the N-terminal part of PrP, specifically residues 112-141, can go through conformational changes involving ␤-strand formation, which subsequently triggers fibril growth (6 -8), and solid state NMR studies showed that residues 112-141 are part of the highly ordered core of huPrP-(23-144) (9). It was previously shown that peptides based on the 89 -143 region of the human PrP protein can form fibrils rich in ␤-sheet structure which are biologically active in transgenic mice (10). Within this region it is the huPrP-(106 -126) peptide that is the smallest known region of PrP that forms fibrils that are toxic and resemble the physiological properties of PrP . The formation of PrP Sc is considered to be a two-step event; first, there is the binding between Pr...

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Section: Resultsmentioning

confidence: 99%

Heterologous Stacking of Prion Protein Peptides Reveals Structural Details of Fibrils and Facilitates Complete Inhibition of Fibril Growth

Boshuizen

Schulz

Morbin

et al. 2009

Journal of Biological Chemistry

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“…The ␤-sheets may instead adopt ␤-helical structures. Amyloids and ␤-helices in general are suggested to share similar motifs (58). Indeed, ␤-helical amyloids are already known for other organisms in various contexts (59 -62).…”

Section: Discussionmentioning

confidence: 96%

The Chlamydia pneumoniae Adhesin Pmp21 Forms Oligomers with Adhesive Properties

Luczak

Smits²,

Decker

et al. 2016

Journal of Biological Chemistry

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“…87 A number of computational studies have also provided insights on the aggregation mechanism of Q/N rich sequences. [88][89][90] The crystal structures of two short peptides NNQQNY and GNNQQNY have been solved. 66 These structures elucidated a 'steric zipper' motif implicated in fibril formation.…”

Section: Prediction Of Potential Aggregation-prone Regionsmentioning

confidence: 99%

“…The role of aromatic residues in promoting aggregation is through the favorable π-stacking interactions; Phe especially is found to form significant homostacking. 88 These interactions lead to aggregates with the specific ordered pattern seen in fibrils. 25,68 surprising because the goal of humanization is to reduce immunogenicity due to foreign origin.…”

Section: Prediction Of Potential Aggregation-prone Regionsmentioning

confidence: 99%

Potential aggregation prone regions in biotherapeutics

Wang

Das

Singh

et al. 2009

mAbs

185

139

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Aggregation of a biotherapeutic is of significant concern and judicious process and formulation development is required to minimize aggregate levels in the final product. Aggregation of a protein in solution is driven by intrinsic and extrinsic factors. In this work we have focused on aggregation as an intrinsic property of the molecule. We have studied the sequences and Fab structures of commercial and non-commercial antibody sequences for their vulnerability towards aggregation by using sequence based computational tools to identify potential aggregation-prone motifs or regions. The mAbs in our dataset contain 2 to 8 aggregation-prone motifs per heavy and light chain pair. Some of these motifs are located in variable domains, primarily in CDRs. Most aggregation-prone motifs are rich in β branched aliphatic and aromatic residues. Hydroxyl-containing Ser/Thr residues are also found in several aggregation-prone motifs while charged residues are rare. The motifs found in light chain CDR3 are glutamine (Q)/asparagine (N) rich. These motifs are similar to the reported aggregation promoting regions found in prion and amyloidogenic proteins that are also rich in Q/N, aliphatic and aromatic residues. The implication is that one possible mechanism for aggregation of mAbs may be through formation of cross-β structures and fibrils. Mapping on the available Fab-receptor/ antigen complex structures reveals that these motifs in CDRs might also contribute significantly towards receptor/antigen binding. Our analysis identifies the opportunity and tools for simultaneous optimization of the therapeutic protein sequence for potency and specificity while reducing vulnerability towards aggregation.

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Sequence and Structure Analysis of Parallel β Helices: Implication for Constructing Amyloid Structural Models

Cited by 40 publications

References 64 publications

Heterologous Stacking of Prion Protein Peptides Reveals Structural Details of Fibrils and Facilitates Complete Inhibition of Fibril Growth

Heterologous Stacking of Prion Protein Peptides Reveals Structural Details of Fibrils and Facilitates Complete Inhibition of Fibril Growth

The Chlamydia pneumoniae Adhesin Pmp21 Forms Oligomers with Adhesive Properties

Potential aggregation prone regions in biotherapeutics

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